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Matching tRNA modifications in humans to their known and predicted enzymes

Valérie de Crécy-Lagard, Pietro Boccaletto, Carl G Mangleburg and 4 more

Nucleic Acids Research · 2019

Abstract

tRNA are post-transcriptionally modified by chemical modifications that affect all aspects of tRNA biology. An increasing number of mutations underlying human genetic diseases map to genes encoding for tRNA modification enzymes. However, our knowledge on human tRNA-modification genes remains fragmentary and the most comprehensive RNA modification database currently contains information on approximately 20% of human cytosolic tRNAs, primarily based on biochemical studies. Recent high-throughput methods such as DM-tRNA-seq now allow annotation of a majority of tRNAs for six specific base modifications. Furthermore, we identified large gaps in knowledge when we predicted all cytosolic and mitochondrial human tRNA modification genes. Only 48% of the candidate cytosolic tRNA modification enzymes have been experimentally validated in mammals (either directly or in a heterologous system). Approximately 23% of the modification genes (cytosolic and mitochondrial combined) remain unknown. We discuss these 'unidentified enzymes' cases in detail and propose candidates whenever possible. Finally, tissue-specific expression analysis shows that modification genes are highly expressed in proliferative tissues like testis and transformed cells, but scarcely in differentiated tissues, with the exception of the cerebellum. Our work provides a comprehensive up to date compilation of human tRNA modifications and their enzymes that can be used as a resource for further studies.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

1The acquisition of post-transcriptional chemical modifications is an essential part of the maturation process required to generate functional tRNA molecules. Modifications have different roles in controlling stability, folding and decoding properties of tRNAs and can be determinants or anti-determinants for other components of the translation apparatus like e.g. aminoacyl-tRNA synthetases. In addition, tRNA modifications can be recognition elements of ribonucleases, leading to the generation of tRNA fragments that affect multiple cellular processes.

2However, very few modifications such as m1G37, Ψ55 or t6A37 are present at a specific position of a particular tRNA in (almost) all known organisms. Most of them are specific to particular taxons, from species to kingdoms. For example, lysidine (k2C34) is a hallmark of bacteria, while archaeosine (G+15) is only found in archaea. Depending on the organism, the total number of genes encoding tRNA modification enzymes varies between as little as eleven in some obligate symbionts to around an estimated hundred in humans of which 50 are currently represented in MODOMICS.

3The near complete sets of tRNA modification genes are currently available for only one organism per domain of life: Saccharomyces cerevisiae for eukarya, where only one gene required for the formation of ncm5U out of cm5U is missing, Escherichia coli for bacteria where only the genes for ho5U34 and Acp3U47-formation remain unidentified and Haloferax volcanii for archaea where a handful of genes are missing. Beyond these three organisms, the annotation of tRNA modification genes remains scarce, because of several issues: First, RNA modification enzymes are often part of large multifunctional protein families such as the Rossmann Fold Methyltransferase (RFM) superfamily, which can act on other substrates than RNA. For example, some RNA methyltransferases are closely related to protein methyltransferases or DNA methyltransferases. Second, closely related members of orthologous families often introduce a similar chemical modification, but in different RNAs and at different positions. For example, members of the TrmFO family methylate tRNA or rRNA depending on the organism. Third, related enzymes can generate chemically distinct modifications. For example closely related Radical-SAM enzymes introduce methyl groups at different positions of nucleosides like in m2A or m8A. Finally, the same chemical modification, in particular methyl groups, can be introduced by proteins that are dissimilar or even evolutionarily unrelated having arisen through non-orthologous gene displacements. For example, the formation of the universal m1G37 is catalyzed by TrmD and Trm5, two enzymes of completely different evolutionary origins in bacteria and in eukarya/archaea. The combination of these factors has made it difficult to identify enzymes responsible for many tRNA modifications and hence to determine the function of those tRNA modifications in many species including humans.

4Recently, an increasing number of mutations causing genetic diseases have been mapped to human genes encoding tRNA modification enzymes (see and Table 1), making a comprehensive list of these genes highly desirable. However, to our knowledge, no complete compilation of modifications found in both cytosolic and mitochondrial human tRNAs with their corresponding predicted or validated modification enzymes is available. For mitochondria, the best approximation is a recent list of modifications of bovine tRNAs and the predicted enzymes, which has been extrapolated for human tRNAs. A prediction of human tRNA methyltransferases, based on the known yeast enzymes was performed more than five years ago and was recently extended to homologs of the other yeast RNA modification genes. Surveys of specific enzyme families such as the human m5C methyltransferases or pseudouridine synthases that target tRNA molecules have listed the known and missing genes for these specific modifications. The goal of our analysis was to compile a comprehensive list of known and predicted tRNA modifications in Homo sapiens with genes implicated in their biosynthesis. This analysis allowed for the identification of the remaining gaps of knowledge in the field of human tRNA modifications and will help to guide future experiments. Furthermore, we have used publicly available datasets in order to determine the expression profiles and proteomic evidence of known and predicted modification enzymes. Our work will facilitate access to the current knowledge on human tRNA modification enzymes for a wider community of biologists.

MATERIALS AND METHODS

5The set of human isoacceptor tRNAs (i.e. tRNAs that are acylated with the same amino acid regardless of the anticodon sequence) was extracted from the Genomic tRNA Database (GtRNAdb): http://gtrnadb.ucsc.edu/ and is summarized here: http://gtrnadb.ucsc.edu/genomes/eukaryota/Hsapi19/

6All modifications present in the sequences of cytosolic and mitochondrial tRNA of human (H. sapiens), cow (Bos taurus), rat (Rattus norvegicus), and mouse (Mus musculus) were extracted from the MODOMICS database of RNA modification pathways (http://modomics.genesilico.pl/). This provided a first list that was then updated with one modification from the literature (m5C34 in Leu-CAA-tRNA) and several human modifications detected with novel tRNAseq methods (m3C20 in Met-CAU-tRNA and m3C47 in Leu-CAG-tRNA and most Ser-tRNAs, m1A16 in mito-Arg-TCG-tRNA and m3C32 in mito-Thr-UGU-tRNA and mito-Ser-UGA) that were missing from MODOMICS. The MODOMICS database was updated accordingly.

7High-throughput tRNA-seq modification data was derived from published study data sets. The protein and literature mining tools of NCBI as well as the Uniprot resource and Id/Mapping tools were used to gather data. Gene names were gathered from the HUGO Gene Nomenclature Committee (https://www.genenames.org). Protein interaction data was derived from BioGrid and the predicted mitochondrial localization from MitoCarta (https://www.broadinstitute.org/files/shared/metabolism/mitocarta/human.mitocarta2.0.html).

8Human co-expression data was extracted from the Search-based Exploration of Expression Compendium (SEEK) database (http://seek.princeton.edu/index.jsp). Phylogenetic trees for specific protein families were extracted from PhylomeDB (http://phylomedb.org). For gene expression analyses, RNAseq data was obtained from the GTEx portal (www.gtexportal.org; GTEx_Analysis_2016-01-15_v7_RNASeQCv1.1.8_gene_tpm.gct.gz) on 30/04/2018. For each gene the transcript with the highest expression levels was selected for each tissue. Subsequently, relative expression levels were calculated and plotted as a heatmap using the heatmap.2 function in R. Tissues included in the analysis were selected to provide a general physiological overview. Hierarchical clustering of genes was performed according to similarity of expression profile using Ward's method. For tissue-specific proteomics evidence, we used the human proteome map (http://www.humanproteomemap.org/) using the default settings. Proteins that were not detected in any tissue were manually removed.

Compiling all mammalian cytosolic tRNA modifications

9As a first step to predict the complete set of modification enzymes, we sought to list the nature and positions of all chemical modifications that have been identified in human cytosolic tRNAs. This task is not trivial as the set of human tRNAs used in decoding is very complex (see for a recent review). Indeed, not all tRNA sequences encoded in the human genome are expressed in common cell-lines. Based on the loss of canonical secondary structure, mutations at highly conserved positions, or positioning in transcriptional silent chromosomal regions, some candidate tRNA genes are likely tRNA-derived Short Interspersed Nuclear Elements or pseudogenes, and others may have non-canonical functions outside of translation. Therefore, additional filtering criteria are needed to select a list of tRNAs that most likely decode mRNAs in the human cytosol. An updated set of ‘high confidence’ human tRNAs has been generated by tRNAscan-SE 2.0 (Chan, Lin and Lowe, unpublished data) and is available in the GtRNAdb. This list of over 400 tRNA genes contains 47 distinct isoacceptors families (including tRNASec, the tRNA for selenocysteine insertion).

10A first set of biochemically-determined tRNA isoacceptor sequences that include chemical modifications in at least one mammal was extracted from the MODOMICS database at the time of the initial analysis (30 May 2017). Furthermore, partial information is available for modifications at specific positions such as wobble uridine (U34). It is known that 5-carbamoylmethyluridine (ncm5U) is found in Val-UAC-tRNA, 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) in Arg-UCU-tRNA and 5-methoxycarbonyl-hydroxymethyluridine (mchm5U) in Gly-UCC-tRNA. Since the modifications of U34 in human Arg-UCU-tRNA and Gly-UCC-tRNA differ from those in the corresponding yeast tRNA, it is difficult to predict the nature of most of the U34 modifications in humans. Finally, a large fraction of the RNA sequence data stems from the 60s, 70s and 80s, so is based on paper and thin-layer chromatography (TLC), photometric characterization of nucleosides following chromatography, and mass-spectrometry using low-resolution, low-sensitivity instruments. These methods failed to identify or distinguish some of the modifications, which are therefore listed as N and xN in Supplementary Table S1A but can now be detected with high-resolution mass spectrometry.

11To add to the complexity of the task, the human genome (in contrast to yeast) encodes isoacceptor families that include many unique isodecoders, which are tRNAs with the same anticodon but contains variations in the tRNA body. Different isodecoders can be expressed under specific conditions as shown for the neuron-specific tRNA-Arg-UCU or in the case of cancer. New high-throughput sequencing methods have been developed and optimized to facilitate detection of full length tRNAs such as DM-tRNA-seq or tRNA-HydroSeq or AlkAniline-Seq and of tRNA-derived small RNAs (ARM-seq). While these high-throughput RNA modification mapping methods reviewed in and are not yet as precise or quantitative as mass spectrometry, they do offer a practical, inexpensive method to survey a subset of modifications across all expressed tRNAs for many cell types. Using these methods also offers a first glimpse of the diversity of modification states across different isodecoders. Some isodecoder families in human such as Ala-AGC can be highly complex, contrasting the relatively simple view previously seen in budding yeast. In human, there are 22 high confidence Ala-AGC tRNA genes detected in the genome, which encode 16 unique (by sequence) Ala-AGC tRNA transcripts; in yeast, there are 11 Ala-AGC genes, which all encode identical Ala-AGC tRNA transcripts. This variation in human tRNA sequences also leads to an apparent complexity in tRNA modifications that is only now being appreciated. For example, RNA modification data collected with traditional methods exists for just 2 out of 16 Ala-AGC isodecoders (Ala-AGC-8 and Ala-AGC-11). ARM-seq and DM-tRNA-seq, however, both detect transcripts and modifications for many more isodecoders (Supplementary Table S5). These high-throughput methods allowed to detect four human modifications that were missing in MODOMICS at the time of our first analysis (see methods section). The final count of tRNA isoacceptors with modification information is 27 in humans and 38 in mammals (Figure 1 and Supplementary Tables S1A and S5).

Linking the modifications of human cytosolic tRNAs to their corresponding modification enzymes

12We generated a current list of chemical modifications found in human cytosolic tRNAs (Figure 2A, Supplementary Table S2) by combining the modification information from the tRNA sequences compiled in Supplementary Table S1A Subsequently, we used this list as a starting point to generate the set of predicted human tRNA modification genes.

13Once the list of human cytosolic tRNA modifications had been generated (Figure 2A, Supplementary Table S2), we linked the modifications to their corresponding modification enzymes whenever possible. This was done by using the advanced query tools of Uniprot for a first pass and then surveying the literature. By default, the reference linking the gene to the function is found by accessing the Uniprot entry for a given gene. Only when the reference had not yet been captured in Uniprot (∼10 cases), did we add a PMID entry in Supplementary Table S2.

14Not all predictions reach the same level of credibility. For example, in some cases, experimental validation is available for the human ortholog, while in other cases only the function of the yeast ortholog is validated. Therefore, we used the following code to classify the evidence of our functional annotation: [5] in vivo data in mammals; [4] in vivo data of the human or a related mammalian enzyme in a heterologous host; [3] in vitro data using the human enzyme; [2] similarity to an experimentally validated gene in a non-mammalian species; [1] candidates that have not been verified in any organism; [0] no clear candidate. These predictions are available in Supplementary Table S2, and we summarized all enzymes with evidence codes 2–5 in Figure 2A, using the protein names recommended by the HUGO Gene Nomenclature committee. According to this assessment, we predicted at least 76 proteins to be required for the modification of cytosolic tRNAs. Clearly, this is an underestimation, as more than 24 enzymes are still unknown (evidence code 0 or 1). Furthermore, for approximately 26 proteins there is no direct in vivo or in vitro experimental data using a mammalian homolog (evidence code 2). Thus, our analysis emphasizes that extensive experimental validations and research will be required to verify specific gene predictions and to identify some of the ‘missing’ genes. These cases will be further discussed below.

Identifying candidates for the ‘missing’ genes

15To identify candidates of unidentified tRNA modifications enzymes, we compiled an initial list of ∼40 human proteins that are members of families known to be implicated in RNA modifications. These were mainly methyltransferases, pseudouridine synthases or THUMP-domain-containing proteins that have not yet been linked to a specific function. When we surveyed the recent literature, we found that ∼2/3 of these candidates had been reported to modify rRNA or proteins. For the remaining twelve proteins/genes, we gathered localization data from Mitocarta, and analyzed co-expression using the SEEK expression database profiles to identify the candidates that are coexpressed with RNA processing or translation related genes (Supplementary Table S4). This list is far from exhaustive as new methylase folds implicated in RNA modification are still being discovered.

Missing genes coding for cytosolic tRNA modification enzymes

16In general, when the gene is missing, the function of the corresponding modification is very difficult to infer, as no genetic study can be conducted. In some cases, such as acp3U20, the gene is not known in any organism, and almost no functional information is available. The only functional inference that can be done is if the gene encoding the enzyme responsible for the same modification is known in another organism. This is the case for a few modifications such as m1A14 and m5U54 in yeast or m1G6 in bacteria and archaea. Also, for complex pathways in which some genes have already been characterized such as Q and mcm5s2U34, functional information is available. However, we feel it is a far stretch to transfer functional inferences made from prokaryotes or unicellular eukaryotes to human. Even if a related enzyme is known in another species, it is very difficult to predict how the unknown human enzyme discriminates substrate tRNAs from non-substrates. Thus, in the absence of information about the gene and enzyme responsible, very little information can be inferred about the function of the modification itself. Below we list modifications of human cytosolic tRNAs, for which the genes remain to be discovered and characterized, and this list also indicates the areas where functional information is missing. m1G6/7: This nucleotide is modified in multiple cytosolic and in at least one mitochondrial tRNA (Supplementary Table S1A and B). Trm14/TrmN are members of the COG0116 family of methyltransferases and target this position in several thermophilic bacteria and archaea. However other members of the same family, such as RmlL have been shown to methylate guanine residues in 23S RNA. THUMPD2 and THUMPD3 are two barely characterized members of this family in humans (Supplementary Table S4), and previous analyses suggested that these enzymes might be required for the formation of both cytosolic and mitochondrial modifications. THUMPD2 was found to form a complex with the m2,2G26-methylase TRMT1, while THUMPD3 was shown to interact with the methylase-activator protein TRM112 in two high-throughput interactome studies, strengthening their role as tRNA methyltransferase candidates. However, experimental verification will be required to evaluate whether these two proteins are essential for the formation of m1G, whether they exhibit different substrates specificities towards G6 or G7 and whether they act in mitochondria or in the cytoplasm.m1A14: Enzymes responsible for this modification were identified in S. cerevisiae and belong to the pfam01746 family. The human genome encodes three members of this family: TRMT10A is required for the generation of m1G9 in cytosolic tRNAs. TRMT10C as part of the RNase P complex, forms m1G9 in mitochondrial tRNAs and like some family members from other species, can also methylate adenosine to form m1A9. Hence, TRMT10B (Supplementary Table S4) is a candidate for the elusive m1A14 methyltransferase, even if a recent report could not detect any tRNA methylation activity in vitro. As expected for a cytosolic enzyme, TRMT10B is not part of the predicted human mitoproteome. However, multiple reports of interactions with 25 mitochondrial ribosomal proteins (https://thebiogrid.org/127659) suggest this protein localizes to the mitochondria. Further experiments will be needed to determine whether TRMT10B is the missing m1A14 methyltransferase or whether TRMT10A methylates both G9 and A14 or whether a yet unknown enzyme catalyzes this reaction.Acp3U20,20a: Only very few enzymes have been characterized that modify RNA by transferring the aminocarboxypropyl (acp) group of SAM, which is the methyl donor in most RNA-methylation reactions. However, acp-transferring enzymes belong to three unrelated superfamilies, which also contain methyltransferases. The only human enzyme currently known to introduce the acp3 modification is TSR3, a member of the COG2042 family, which is required for the biosynthesis of the hypermodified nucleotide m1acp3Ψ in 18S rRNA. The crystal structures of its archaeal homologs revealed that TSR3 belongs to the SPOUT class of methyltransferases. The second structurally characterized acp-transferase Tyw2 belongs to the unrelated RFM superfamily. A different acp modification has been described in the diphthamide-biosynthesis pathway, where an acp group is transferred from SAM to the carbon atom of a histidine residue of eukaryotic translation elongation factor 2 (eEF2) by an enzyme that belongs to the Radical-SAM superfamily. acp3U is found in several positions in tRNA of different organisms like for example acp3U47 in E. coli tRNA, but the corresponding enzymes have not been identified in any of these species. Since all known acp transferases most likely arose independently from methyltransferases, the acp3U-forming enzyme may currently be annotated as a hypothetical methyltransferase of unknown function (Supplementary Table S4) but it is difficult to select a plausible candidate in light of the diversity of known acp transferases.Ψ: The list of pseudouridine synthases modifying human tRNAs is far from complete. Several candidates have been proposed to be required for the modification of positions 30–32, 50, 72 or e11,12,13, but several can likely be excluded as they were found to be required for the modification of mitochondrial rRNA and mito-tRNA at positions 27, 29, 39 and 50 (RPUSD4) or mitochondrial mRNA (like RPUSD3). RPUSD1 and RPUSD2 (Supplementary Table S4) have not been tested experimentally and are hence still valid candidates. Pus7/TruD, the enzyme that introduces Ψ13 is highly conserved in all three kingdoms and is a member of the COG0585 family. The yeast Pus7 enzyme further modifies position 35. PUS7 and PUS7L, two members of the COG0585 family in humans are products of a gene duplication that occurred most certainly in the common ancestors of metazoa (see http://phylomedb.org/?q=search_tree&seqid=Q9H0K6). Experiments will be required to determine whether these two enzymes have identical, overlapping or different substrates specificities. For example, one of the two enzymes might modify position 13, while the second enzyme might target position 35. Another possibility is that PUS7 and PUS7L target both positions 13 and 35, but in different tRNA isoacceptors. PUS7 is implicated in pseudouridylation of Ψ8 in tRF derived from Ala-tRNA, Cys-tRNA and Val-tRNA but whether PUS7 acts directly on tRNA has formally not been shown. PUS1 is multisite specific so it is a plausible candidate for the positions 30 to 32, even though it has been found that the mouse homolog modifies positions 27, 28, 34 and 36. Finally, based on experimental evidence from Archaea, it had been postulated that the human Pus10 is required for the formation of Ψ54 and this was recently experimental validated in human.Q34: Queuosine in position 34 (Q34) is highly conserved in bacteria and eukarya. Humans like all eukaryotes are unable to synthesize Q but instead salvage the queuine (q) base from their diet and gut microflora as a micronutrient. Recent studies have shown that nutritionally determined Q-tRNA levels promote Dnmt2-mediated methylation of tRNA-Asp and control translational speed of Q-decoded codons as well as at near-cognate codons. The heterodimeric human TGT enzyme formed by the QTRT1 and QTRT2 (previously called QTRTD1) subunits is the only fully characterized enzyme of the Q salvage pathway. A second human salvage-enzyme member of the DUF2419 family has been identified but its molecular function is unknown. Finally, the transporter for the q base or the precursor nucleoside Q is still elusive as well as the enzyme(s) that further modify the Q residue by attaching galactosyl or mannosyl moieties.mcm5s2U34: Wobble uridine is generally modified in all known organisms (see for a recent review). The combination of modifications at positions 2 and 5 of the nucleobase results in an intricate tuning of codon-anticodon interactions, thus allowing the translation apparatus to distinguish codons in split-codon boxes and to introduce additional amino acids. 5-carboxymethyluridine (cm5U), the first step of the 5-modification is introduced by the action of the Elongator complex, a heteromeric complex consisting of two copies of Elp1–Elp6 that is activated by several auxiliary proteins. Orthologs of all yeast Elongator complex subunits are known and described in humans. However, human orthologs of the yeast regulatory components (the kinase Kti14, the phosphatase Sit4 and its regulatory subunits Sap185 and Sap190) could not be identified. Here, functional screens will be required to determine the counterparts of these components in humans. The conversion of cm5U to mcm5U is catalyzed by the c-terminal Trm9 domain of ALKBH8. mcm5U in some tRNA can be further hydroxylated to mchm5U by the AlkB Domain of ALKBH8 or 2′-O-methylated to mcm5Um by an unknown enzyme. The enzyme required for ncm5U formation from cm5U is not known in any organism and remains to be identified. 2-thiolation is achieved through the action of the URM1 pathway that shares features of bacterial sulfur-carrier proteins (SCP) and ubiquitin-like proteins (UBL). The URM1 pathway components are straight forward to identify. Urm1 has two homologs in humans: URM1 and MOCS2A. However, MOCS2A is required for the synthesis of the molybdopterin cofactor while URM1 is required for tRNA thiolation and MOCS3 activates the SCP of both pathways. The final step of the thiolation reaction is performed by a complex consisting of CTU1 and CTU2.Missing methyltransferases. Methyltransferases are the biggest group of RNA modifying enzymes. While many tRNA methyltransferases have been discovered and characterized, a few of them remain to be identified (Supplementary Table S2). Members of the NSUN family (PF01189) usually introduce m5C modifications and some such as NSUN2 are multi-site specific. However, NSUN2 is not required for the formation of m5C40 or m5C72. NSUN7 is the only member of the NSUN family without a known substrate (Supplementary Table S4). Hence, it is a strong candidate for methylating one or both these positions. However, indirect data links it to methylation of enhancer RNAs. Three enzymes (METTL2A, METTL2B and METTL6) have been found to be involved in m3C32 formation potentially on different tRNA targets. Any of these three might be required for introducing m3C at position e2 and/or 47 as the biochemical assays have been inconclusive to date (See, Supplementary Table S5). It is unclear, which protein synthesizes m5U54 since two human homologs of yeast Trm2 were identified: TRMT2A and TRMT2B (Supplementary Table S2). It is not known whether these two proteins catalyze the same reaction or whether they differ in substrate specificity or sub-cellular localization. For example, TRMT2B is predicted to localize to mitochondria and might be required for modifying mitochondrial tRNAs (Supplementary Table S3). Finally, no candidate can easily be proposed for the formation of m1Ψ39, Ψm39 and Gm39. The pool of methyltransferase candidates among proteins with uncharacterized functions is large (∼8, Supplementary Table S4), and we did not find evidence to favor a specific candidate.

17m1G6/7: This nucleotide is modified in multiple cytosolic and in at least one mitochondrial tRNA (Supplementary Table S1A and B). Trm14/TrmN are members of the COG0116 family of methyltransferases and target this position in several thermophilic bacteria and archaea. However other members of the same family, such as RmlL have been shown to methylate guanine residues in 23S RNA. THUMPD2 and THUMPD3 are two barely characterized members of this family in humans (Supplementary Table S4), and previous analyses suggested that these enzymes might be required for the formation of both cytosolic and mitochondrial modifications. THUMPD2 was found to form a complex with the m2,2G26-methylase TRMT1, while THUMPD3 was shown to interact with the methylase-activator protein TRM112 in two high-throughput interactome studies, strengthening their role as tRNA methyltransferase candidates. However, experimental verification will be required to evaluate whether these two proteins are essential for the formation of m1G, whether they exhibit different substrates specificities towards G6 or G7 and whether they act in mitochondria or in the cytoplasm.

18m1A14: Enzymes responsible for this modification were identified in S. cerevisiae and belong to the pfam01746 family. The human genome encodes three members of this family: TRMT10A is required for the generation of m1G9 in cytosolic tRNAs. TRMT10C as part of the RNase P complex, forms m1G9 in mitochondrial tRNAs and like some family members from other species, can also methylate adenosine to form m1A9. Hence, TRMT10B (Supplementary Table S4) is a candidate for the elusive m1A14 methyltransferase, even if a recent report could not detect any tRNA methylation activity in vitro. As expected for a cytosolic enzyme, TRMT10B is not part of the predicted human mitoproteome. However, multiple reports of interactions with 25 mitochondrial ribosomal proteins (https://thebiogrid.org/127659) suggest this protein localizes to the mitochondria. Further experiments will be needed to determine whether TRMT10B is the missing m1A14 methyltransferase or whether TRMT10A methylates both G9 and A14 or whether a yet unknown enzyme catalyzes this reaction.

19Acp3U20,20a: Only very few enzymes have been characterized that modify RNA by transferring the aminocarboxypropyl (acp) group of SAM, which is the methyl donor in most RNA-methylation reactions. However, acp-transferring enzymes belong to three unrelated superfamilies, which also contain methyltransferases. The only human enzyme currently known to introduce the acp3 modification is TSR3, a member of the COG2042 family, which is required for the biosynthesis of the hypermodified nucleotide m1acp3Ψ in 18S rRNA. The crystal structures of its archaeal homologs revealed that TSR3 belongs to the SPOUT class of methyltransferases. The second structurally characterized acp-transferase Tyw2 belongs to the unrelated RFM superfamily. A different acp modification has been described in the diphthamide-biosynthesis pathway, where an acp group is transferred from SAM to the carbon atom of a histidine residue of eukaryotic translation elongation factor 2 (eEF2) by an enzyme that belongs to the Radical-SAM superfamily. acp3U is found in several positions in tRNA of different organisms like for example acp3U47 in E. coli tRNA, but the corresponding enzymes have not been identified in any of these species. Since all known acp transferases most likely arose independently from methyltransferases, the acp3U-forming enzyme may currently be annotated as a hypothetical methyltransferase of unknown function (Supplementary Table S4) but it is difficult to select a plausible candidate in light of the diversity of known acp transferases.

20Ψ: The list of pseudouridine synthases modifying human tRNAs is far from complete. Several candidates have been proposed to be required for the modification of positions 30–32, 50, 72 or e11,12,13, but several can likely be excluded as they were found to be required for the modification of mitochondrial rRNA and mito-tRNA at positions 27, 29, 39 and 50 (RPUSD4) or mitochondrial mRNA (like RPUSD3). RPUSD1 and RPUSD2 (Supplementary Table S4) have not been tested experimentally and are hence still valid candidates. Pus7/TruD, the enzyme that introduces Ψ13 is highly conserved in all three kingdoms and is a member of the COG0585 family. The yeast Pus7 enzyme further modifies position 35. PUS7 and PUS7L, two members of the COG0585 family in humans are products of a gene duplication that occurred most certainly in the common ancestors of metazoa (see http://phylomedb.org/?q=search_tree&seqid=Q9H0K6). Experiments will be required to determine whether these two enzymes have identical, overlapping or different substrates specificities. For example, one of the two enzymes might modify position 13, while the second enzyme might target position 35. Another possibility is that PUS7 and PUS7L target both positions 13 and 35, but in different tRNA isoacceptors. PUS7 is implicated in pseudouridylation of Ψ8 in tRF derived from Ala-tRNA, Cys-tRNA and Val-tRNA but whether PUS7 acts directly on tRNA has formally not been shown. PUS1 is multisite specific so it is a plausible candidate for the positions 30 to 32, even though it has been found that the mouse homolog modifies positions 27, 28, 34 and 36. Finally, based on experimental evidence from Archaea, it had been postulated that the human Pus10 is required for the formation of Ψ54 and this was recently experimental validated in human.

21Q34: Queuosine in position 34 (Q34) is highly conserved in bacteria and eukarya. Humans like all eukaryotes are unable to synthesize Q but instead salvage the queuine (q) base from their diet and gut microflora as a micronutrient. Recent studies have shown that nutritionally determined Q-tRNA levels promote Dnmt2-mediated methylation of tRNA-Asp and control translational speed of Q-decoded codons as well as at near-cognate codons. The heterodimeric human TGT enzyme formed by the QTRT1 and QTRT2 (previously called QTRTD1) subunits is the only fully characterized enzyme of the Q salvage pathway. A second human salvage-enzyme member of the DUF2419 family has been identified but its molecular function is unknown. Finally, the transporter for the q base or the precursor nucleoside Q is still elusive as well as the enzyme(s) that further modify the Q residue by attaching galactosyl or mannosyl moieties.

22mcm5s2U34: Wobble uridine is generally modified in all known organisms (see for a recent review). The combination of modifications at positions 2 and 5 of the nucleobase results in an intricate tuning of codon-anticodon interactions, thus allowing the translation apparatus to distinguish codons in split-codon boxes and to introduce additional amino acids. 5-carboxymethyluridine (cm5U), the first step of the 5-modification is introduced by the action of the Elongator complex, a heteromeric complex consisting of two copies of Elp1–Elp6 that is activated by several auxiliary proteins. Orthologs of all yeast Elongator complex subunits are known and described in humans. However, human orthologs of the yeast regulatory components (the kinase Kti14, the phosphatase Sit4 and its regulatory subunits Sap185 and Sap190) could not be identified. Here, functional screens will be required to determine the counterparts of these components in humans. The conversion of cm5U to mcm5U is catalyzed by the c-terminal Trm9 domain of ALKBH8. mcm5U in some tRNA can be further hydroxylated to mchm5U by the AlkB Domain of ALKBH8 or 2′-O-methylated to mcm5Um by an unknown enzyme. The enzyme required for ncm5U formation from cm5U is not known in any organism and remains to be identified. 2-thiolation is achieved through the action of the URM1 pathway that shares features of bacterial sulfur-carrier proteins (SCP) and ubiquitin-like proteins (UBL). The URM1 pathway components are straight forward to identify. Urm1 has two homologs in humans: URM1 and MOCS2A. However, MOCS2A is required for the synthesis of the molybdopterin cofactor while URM1 is required for tRNA thiolation and MOCS3 activates the SCP of both pathways. The final step of the thiolation reaction is performed by a complex consisting of CTU1 and CTU2.

23Missing methyltransferases. Methyltransferases are the biggest group of RNA modifying enzymes. While many tRNA methyltransferases have been discovered and characterized, a few of them remain to be identified (Supplementary Table S2). Members of the NSUN family (PF01189) usually introduce m5C modifications and some such as NSUN2 are multi-site specific. However, NSUN2 is not required for the formation of m5C40 or m5C72. NSUN7 is the only member of the NSUN family without a known substrate (Supplementary Table S4). Hence, it is a strong candidate for methylating one or both these positions. However, indirect data links it to methylation of enhancer RNAs. Three enzymes (METTL2A, METTL2B and METTL6) have been found to be involved in m3C32 formation potentially on different tRNA targets. Any of these three might be required for introducing m3C at position e2 and/or 47 as the biochemical assays have been inconclusive to date (See, Supplementary Table S5). It is unclear, which protein synthesizes m5U54 since two human homologs of yeast Trm2 were identified: TRMT2A and TRMT2B (Supplementary Table S2). It is not known whether these two proteins catalyze the same reaction or whether they differ in substrate specificity or sub-cellular localization. For example, TRMT2B is predicted to localize to mitochondria and might be required for modifying mitochondrial tRNAs (Supplementary Table S3). Finally, no candidate can easily be proposed for the formation of m1Ψ39, Ψm39 and Gm39. The pool of methyltransferase candidates among proteins with uncharacterized functions is large (∼8, Supplementary Table S4), and we did not find evidence to favor a specific candidate.

Identification of the genes encoding for mitochondrial tRNA modifications enzymes

24The Suzuki laboratory published a thorough compilation of tRNA modification enzymes for the full set of 22 bovine mito-tRNAs and most of their functional annotations can be transferred to orthologous human enzymes (Figure 2B, Supplementary Table S3). Furthermore, some open cases have been solved since. Notably, ALKBH1 and NSUN3 are required for the formation of f5C in initiator tRNA. The same ALKBH1 enzyme is further required for hm5C and f5C formation in cytosolic tRNA. A more complete compilation of the predicted human mitochondrial tRNA modification enzymes was published recently with extensive added functional information. We compiled these predictions and added evidence codes resulting in a list of 35 enzymes required to modify the full set of mitochondrial tRNAs (Figure 2B and Supplementary Table S3). An additional evidence code to classify enzymes that have been experimentally validated in the cytoplasm but not in mitochondria was added (evidence code 6). We will discuss here the remaining open questions.

25The Q base is found in mitochondrial tRNAs and the catalytic subunit QTRT1 of the human transglycosylase complex is found in the mitoproteome (Supplementary Table S3). In the cytoplasm, QTRT1 forms a complex with QTRT2 but it is not known whether this interaction also occurs in mitochondria. It has been shown that QTRT1 and QTRT2 are associated with the mitochondria with QTRT2 more loosely bound than QTRT1. Is it possible that QTRT2 facilitates the transport of q, as the mitochondrial queuine transporter is missing?

26Similar to cytosolic pseudourine synthases, the set of enzymes introducing Ψ residues in mitochondrial tRNAs is far from complete, in particular since different enzymes can introduce the same modification at a given position in different tRNAs, implying that many more might be missing. RPUSD4 was recently shown to modify 16S rRNA from mitochondria and introduce Ψ39 in mito-tRNAPhe but not in mito-tRNAGly. PUS3 was predicted to modify other mitochondrial tRNAs such as mito-tRNAGln at position 39. However, experimental data on PUS3 is available only for cytosolic tRNAs, requiring additional confirmation of its mitochondrial targets. Two pseudouridine synthases without known substrates (RPUSD3 and PUS1L) localize to the mitochondria (Supplementary Table S4). RUPSD3 modifies mitochondrial mRNAs, leaving PUS1L as a strong candidate for an enzyme that modifies positions 30, 31, 50 and/or 57 (Supplementary Table S4). Nevertheless, we cannot exclude that a pseudouridine synthase not predicted to be mitochondrial such as RPUSD1 or RPSUD2 is actually dually-targeted as it has been recently shown for Pus10 that is translocated to the mitochondria only under specific physiological conditions.

27In general, the situation is more complex when one gene encodes for two proteins that localize to different sub-cellular compartments, since the mitochondria-targeted isoform is often not identified as a mitochondrial protein. Thirty- seven proteins are predicted to be required for mitochondrial tRNA modifications with nine of these currently unknown, and eleven modify only mitochondrial tRNAs (Supplementary Table S3). In the Mitocarta analysis that integrates 14 different sources of predictions and experimental data to compile a list 1158 human mitochondrial protein, ten of these proteins were correctly identified as mitochondrial (Supplementary Table S3). The only exception is CDK5RAP1, an enzyme required for the thiolation reaction during ms2i6A formation. Of the dually targeted proteins, ten were correctly assigned as mitochondrial in Mitocarta (Supplementary Table S3) while seven others were not: TRM5, YRDC, PUS3, NSUN2, TRM112, METTL2B and QTRT2. TRM112 and QTRT2 are non-catalytic subunits and it cannot be excluded that they are dispensable in mitochondria, as tRNA modification machineries can be simpler in mitochondria. For example, only two proteins are required for the synthesis of t6A in mitochondria while six proteins are required in the cytosol. The case of PUS3 has already been discussed above. For the remaining three cases, dual localization data in yeast for Sua5p and for Trm5p as well as predicted isoforms (see http://www.uniprot.org/uniprot/Q08J23 for NSUN2) suggest that they can be similarly found in both compartments in humans. Hence, the MitoCarta set of mitochondrial proteins may be incomplete.

28Finally, the enzymes required for the formation of m2G6, m5C72 and of several Ψ residues are experimentally uncharacterized (Supplementary Table S3). As discussed above, the two candidates for the formation of cytosolic m2G6 are THUMPD2 and THUMPD3. These two proteins are not predicted to localize to mitochondria but this prediction might not be correct. The same is true for the candidate for the cytosolic m5C72 methylase, NSUN7.

Tissue expression and proteomics data of tRNA modification enzymes

29Disease phenotypes of aberrant tRNA modification enzymes are often linked to neuronal phenotypes, metabolic disorders and cancer. However, the tissue-specific expression profiles of tRNA modification genes have not been systematically explored. Therefore, we used expression data available through the Genotype-Tissue-Expression (GTEx) project and compared expression levels of all modification genes in representative tissues of all organs (Figure 3). We also compiled tissue-specific proteomics evidence from the human proteome map (Supplementary Figure S1). Overall, there are several general trends: First, expression levels of modification genes are quite uniform between different tissues. Second, expression levels of most genes are relatively low, in particular in whole blood. Third, generally high expression levels are observed in testis and transformed cells. Fourth, expression levels in brain are below average of the tissues with the exception of the cerebellum, where expression of a small number of genes reaches levels that are similar to expression observed in testis. This is surprising given the typical neuronal phenotypes observed upon defects in human modification enzymes. There are, however, clusters of genes that are upregulated in several brain tissues (Figure 3). These findings may point to a more crucial function during early steps of differentiation and proliferation of stem cells. Thus, it is likely that many of the observed defects in humans are either developmental phenotypes or relatively subtle. Finally, even though most genes of different pathways are found in similar clusters, this is not true for all pathways, e.g. the ELP pathway. A similar trend is seen when analyzing the proteomics data (Supplementary Figure S1). With the highly expressed genes, a correlation was observed between the transcriptomic and proteomics data (for example DUS2, PUS3 or TRMT5 in testis), however, the proteomic data is less complete due to the low expression levels of most enzymes (Supplementary Figure S1). These observations suggest that tRNA modification enzymes are able to maintain sufficiently high modification levels in differentiated tissues likely because of the high stability of tRNA and low tRNA synthesis levels. Furthermore, some modification enzymes bind to RNA that are not their natural targets (See for specific examples). Hence, it is likely beneficial to maintain low expression levels of these enzymes to avoid unspecific modification of cellular RNA like mRNA or rRNA.

CONCLUSIONS

30This inventory of human tRNA modifications and the corresponding enzymes surprisingly reveals that despite the fact that the field of RNA modifications has dramatically expanded in recent years with 50 human modifications enzymes identified only in the last 10 years, the picture is far from complete. We estimate that between ∼135 genes are required to modify cytosolic and mitochondrial tRNAs and that 23% of these genes still need to be identified and that another 22% require further experimental validations. Approximately 50% of the human modification genes have been linked to a number of human diseases (Table 1). Furthermore, all genes required for the formation of iron-sulfur clusters affect tRNA modification indirectly and are linked to diseases that are likely not mediated by tRNA modification defects. Like described before the phenotypes are most often neurodegenerative or neurodevelopmental diseases like microcephaly and intellectual disabilities, but also renal and metabolic defects. Finally, roughly 50% of the disease genes have been linked to cancer (Table 1), suggesting that tRNA modification enzymes may provide interesting targets for cancer therapies. Also, given the wide diversity of tRNA transcript sequences in humans, the preference of different members of the modification enzyme families for different tRNA isodecoders remains an open question. An in-depth analysis of tRNA modification dynamics in various stress conditions and cell types will reveal the intimate relationship between tRNAs and their modifying partners in more detail. This compilation can act as a guide for future experiments to complete the characterization of the set of human tRNA modification enzymes.

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Not in our library10.1093/nar/gky931
68.
Armengaud J., Dedieu A., Solques O., Pellequer J.L., Quemeneur E. Deciphering structure and topology of conserved COG2042 orphan proteins. BMC Struct. Biol.2005; 5:3.
Not in our library10.1186/1472-6807-5-3
69.
Meyer B., Wurm J.P., Sharma S., Immer C., Pogoryelov D., Kötter P., Lafontaine D.L.J., Wöhnert J., Entian K.D. Ribosome biogenesis factor Tsr3 is the aminocarboxypropyl transferase responsible for 18S rRNA hypermodification in yeast and humans. Nucleic Acids Res.2016; 44:4304–4316.
Not in our library10.1093/nar/gkw244
70.
Umitsu M., Nishimasu H., Noma A., Suzuki T., Ishitani R., Nureki O. Structural basis of AdoMet-dependent aminocarboxypropyl transfer reaction catalyzed by tRNA-wybutosine synthesizing enzyme, TYW2. Proc. Natl. Acad. Sci. U.S.A.2009; 106:15616–15621.
Not in our library10.1073/pnas.0905270106
71.
Schaffrath R., Abdel-Fattah W., Klassen R., Stark M.J.R. The diphthamide modification pathway from Saccharomyces cerevisiae - revisited. Mol. Microbiol.2014; 94:1213–1226.
Not in our library10.1111/mmi.12845
72.
Zaganelli S., Rebelo-Guiomar P., Maundrell K., Rozanska A., Pierredon S., Powell C.A., Jourdain A.A., Hulo N., Lightowlers R.N., Chrzanowska-Lightowlers Z.M. et al. The pseudouridine synthase RPUSD4 is an essential component of mitochondrial RNA granules. J. Biol. Chem.2017; 292:4519–4532.
Not in our library10.1074/jbc.m116.771105
73.
Antonicka H., Choquet K., Lin Z., Gingras A., Kleinman C.L., Shoubridge E.A. A pseudouridine synthase module is essential for mitochondrial protein synthesis and cell viability. EMBO Rep.2017; 18:28–38.
Not in our library10.15252/embr.201643391
74.
Kaya Y., Ofengand J. A novel unanticipated type of pseudouridine synthase with homologs in bacteria, archaea, and eukarya. RNA. 2003; 9:711–721.
Not in our library10.1261/rna.5230603
75.
Urban A., Behm-Ansmant I., Branlant C., Motorin Y. RNA sequence and two-dimensional structure features required for efficient substrate modification by the Saccharomyces cerevisiae RNA:Ψ-synthase Pus7p. J. Biol. Chem.2009; 284:5845–5858.
Not in our library10.1074/jbc.m807986200
76.
Guzzi N., Cieśla M., Ngoc P.C.T., Lang S., Arora S., Dimitriou M., Pimková K., Sommarin M.N.E., Munita R., Lubas M. et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell. 2018; 173:1204–1216.
Not in our library10.1016/j.cell.2018.03.008
77.
Behm-Ansmant I., Massenet S., Immel F., Patton J.R., Motorin Y., Branlant C. A previously unidentified activity of yeast and mouse RNA: pseudouridine synthases 1 (Pus1p) on tRNAs. RNA. 2006; 12:1583–1593.
Not in our library10.1261/rna.100806
78.
Joardar A., Jana S., Fitzek E., Gurha P., Majumder M., Chatterjee K., Geisler M., Gupta R. Role of forefinger and thumb loops in production of Ψ54 and Ψ55 in tRNAs by archaeal Pus10. RNA. 2013; 19:1279–1294.
Not in our library10.1261/rna.039230.113
79.
Deogharia M., Mukhopadhyay S., Joardar A., Gupta R. The human ortholog of archaeal Pus10 produces pseudouridine 54 in select tRNAs where its recognition sequence contains a modified residue. RNA. 2018; doi:10.1261/rna.068114.118.
Not in our library10.1261/rna.068114.118
80.
The Queuine Micronutrient: Charting a Course from Microbe to Man · 2015
No notice
81.
Tuorto F., Legrand C., Cirzi C., Federico G., Liebers R., Müller M., Ehrenhofer-Murray A.E., Dittmar G., Gröne H.-J., Lyko F. Queuosine-modified tRNAs confer nutritional control of protein translation. EMBO J.2018; 37:e99777.
Not in our library10.15252/embj.201899777
82.
Zallot R., Brochier-Armanet C., Gaston K.W., Forouhar F., Limbach P.A., Hunt J.F., de Crécy-Lagard V. Plant, animal, and fungal micronutrient queuosine is salvaged by members of the DUF2419 protein family. ACS Chem. Biol.2014; 9:1812–1825.
Not in our library10.1021/cb500278k
83.
Schaffrath R., Leidel S.A. Wobble uridine modifications–a reason to live, a reason to die?. RNA Biol.2017; 14:1209–1222.
Not in our library10.1080/15476286.2017.1295204
84.
Grosjean H., Westhof E. An integrated, structure- and energy-based view of the genetic code. Nucleic Acids Res.2016; 44:8020–8040.
Not in our library10.1093/nar/gkw608
85.
Dauden M.I., Jaciuk M., Müller C.W., Glatt S. Structural asymmetry in the eukaryotic Elongator complex. FEBS Lett.2018; 592:502–515.
Not in our library10.1002/1873-3468.12865
86.
Fu D., Brophy J.A.N., Chan C.T.Y., Atmore K.A., Begley U., Paules R.S., Dedon P.C., Begley T.J., Samson L.D. Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival. Mol. Cell. Biol.2010; 30:2449–2459.
Not in our library10.1128/mcb.01604-09
87.
Fu Y., Dai Q., Zhang W., Ren J., Pan T., He C. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA. Angew. Chem. Int. Ed. Engl.2010; 49:8885–8888.
Not in our library10.1002/anie.201001242
88.
Songe-Møller L., van den Born E., Leihne V., Vågbø C.B., Kristoffersen T., Krokan H.E., Kirpekar F., Falnes P.Ø., Klungland A. Mammalian ALKBH8 possesses tRNA methyltransferase activity required for the biogenesis of multiple wobble uridine modifications implicated in translational decoding. Mol. Cell. Biol.2010; 30:1814–1827.
Not in our library10.1128/mcb.01602-09
89.
Termathe M., Leidel S.A. The Uba4 domain interplay is mediated via a thioester that is critical for tRNA thiolation through Urm1 thiocarboxylation. Nucleic Acids Res.2018; 46:5171–5181.
Not in our library10.1093/nar/gky312
90.
Chowdhury M.M., Dosche C., Löhmannsröben H.-G., Leimkühler S. Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. J. Biol. Chem.2012; 287:17297–17307.
Not in our library10.1074/jbc.m112.351429
91.
Bujnicki J.M., Feder M., Ayres C.L., Redman K.L. Sequence-structure-function studies of tRNA:m5C methyltransferase Trm4p and its relationship to DNA:m5C and RNA:m5U methyltransferases. Nucleic Acids Res.2004; 32:2453–2463.
Not in our library10.1093/nar/gkh564
92.
Auxilien S., Guérineau V., Szweykowska-Kuliñska Z., Golinelli-Pimpaneau B. The human tRNA m5C methyltransferase Misu is multisite-specific. RNA Biol.2012; 9:1331–1338.
Not in our library10.4161/rna.22180
93.
Aguilo F., Li S. De, Balasubramaniyan N., Sancho A., Benko S., Zhang F., Vashisht A., Rengasamy M., Andino B., Chen C. hung et al. Deposition of 5-methylcytosine on enhancer RNAs enables the coactivator function of PGC-1α. Cell Rep.2016; 14:479–492.
Not in our library10.1016/j.celrep.2015.12.043
94.
Xu L., Liu X., Sheng N., Oo K.S., Liang J., Chionh Y.H., Xu J., Ye F., Gao Y.-G., Dedon P.C. et al. Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans. J. Biol. Chem.2017; 292:14695–14703.
Not in our library10.1074/jbc.m117.798298
95.
Kawarada L., Suzuki T., Ohira T., Hirata S., Miyauchi K., Suzuki T. ALKBH1 is an RNA dioxygenase responsible for cytoplasmic and mitochondrial tRNA modifications. Nucleic Acids Res.2017; 45:7401–7415.
Not in our library10.1093/nar/gkx354
96.
Haag S., Sloan K.E., Ranjan N., Warda A.S., Kretschmer J., Blessing C., Hübner B., Seikowski J., Dennerlein S., Rehling P. et al. NSUN3 and ABH1 modify the wobble position of mt‐tRNA Met to expand codon recognition in mitochondrial translation. EMBO J.2016; 35:2104–2119.
Not in our library10.15252/embj.201694885
97.
Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3 · 2016
No notice
98.
Chen Y.C., Kelly V.P., Stachura S. V., Garcia G.A. Characterization of the human tRNA-guanine transglycosylase: confirmation of the heterodimeric subunit structure. RNA. 2010; 16:958–968.
Not in our library10.1261/rna.1997610
99.
Boland C., Hayes P., Santa-Maria I., Nishimura S., Kelly V.P. Queuosine formation in eukaryotic tRNA occurs via a mitochondria-localized heteromeric transglycosylase. J. Biol. Chem.2009; 284:18218–18227.
Not in our library10.1074/jbc.m109.002477
100.
Jana S., Hsieh A.C., Gupta R. Reciprocal amplification of caspase-3 activity by nuclear export of a putative human RNA-modifying protein, PUS10 during TRAIL-induced apoptosis. Cell Death Dis.2017; 8:e3093.
Not in our library10.1038/cddis.2017.476
101.
Wei F.Y., Zhou B., Suzuki T., Miyata K., Ujihara Y., Horiguchi H., Takahashi N., Xie P., Michiue H., Fujimura A. et al. Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Cell Metab.2015; 21:428–442.
Not in our library10.1016/j.cmet.2015.01.019
102.
Fakruddin M., Wei F.Y., Emura S., Matsuda S., Yasukawa T., Kang D., Tomizawa K. Cdk5rap1-mediated 2-methylthio-N6-isopentenyladenosine modification is absent from nuclear-derived RNA species. Nucleic Acids Res.2017; 45:11954–11961.
Not in our library10.1093/nar/gkx819
103.
Thiaville P.C., Iwata-Reuyl D., DeCrécy-Lagard V. Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t6A), a universal modification of tRNA. RNA Biol.2014; 11:1529–1539.
Not in our library10.4161/15476286.2014.992277
104.
Thiaville P.C., Yacoubi B. El, Perrochia L., Hecker A., Prigent M., Thiaville J.J., Forterre P., Namy O., Basta T., de Crécy-Lagard V. Cross kingdom functional conservation of the core universally conserved threonylcarbamoyladenosine tRNA synthesis enzymes. Eukaryot. Cell. 2014; 13:1222–1231.
Not in our library10.1128/ec.00147-14
105.
Lee C., Kramer G., Graham D.E., Appling D.R. Yeast mitochondrial initiator tRNA is methylated at guanosine 37 by the Trm5-encoded tRNA (guanine-N1-)-methyltransferase. J. Biol. Chem.2007; 282:27744–27753.
Not in our library10.1074/jbc.m704572200
106.
Leidel S., Pedrioli P.G.A., Bucher T., Brost R., Costanzo M., Schmidt A., Aebersold R., Boone C., Hofmann K., Peter M. Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA. Nature. 2009; 458:228–232.
Not in our library10.1038/nature07643
107.
Waller T.J., Read D.F., Engelke D.R., Smaldino P.J. The human tRNA-modifying protein, TRIT1, forms amyloid fibers in vitro. Gene. 2017; 612:19–24.
Not in our library10.1016/j.gene.2016.10.041
108.
Pratt-Hyatt M., Pai D.A., Haeusler R.A., Wozniak G.G., Good P.D., Miller E.L., McLeod I.X., Yates J.R., Hopper A.K., Engelke D.R. Mod5 protein binds to tRNA gene complexes and affects local transcriptional silencing. Proc. Natl. Acad. Sci. U.S.A.2013; 110:E3081–E3089.
Not in our library10.1073/pnas.1219946110
109.
Keffer-Wilkes L.C., Veerareddygari G.R., Kothe U. RNA modification enzyme TruB is a tRNA chaperone. Proc. Natl. Acad. Sci. U.S.A.2016; 113:14306–14311.
Not in our library10.1073/pnas.1607512113
110.
Murphy M., Docherty N.G., Griffin B., Howlin J., McArdle E., McMahon R., Schmid H., Kretzler M., Droguett A., Mezzano S. et al. IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis. J. Am. Soc. Nephrol.2008; 19:1672–1680.
Not in our library10.1681/asn.2007101080
111.
Cosentino C., Toivonen S., Diaz Villamil E., Atta M., Ravanat J.-L., Demine S., Schiavo A.A., Pachera N., Deglasse J.-P., Jonas J.-C. et al. Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Res.2018; 46:10302–10318.
Not in our library10.1093/nar/gky839
112.
Zhang H., Hou W., Wang H.-L., Liu H.-J., Jia X.-Y., Zheng X.-Z., Zou Y.-X., Li X., Hou L., McNutt M.A. et al. GSK-3β-regulated N-acetyltransferase 10 is involved in colorectal cancer invasion. Clin. Cancer Res.2014; 20:4717–4729.
Not in our library10.1158/1078-0432.ccr-13-3477
113.
Zhang X., Jiang G., Sun M., Zhou H., Miao Y., Liang M., Wang E., Zhang Y. Cytosolic THUMPD1 promotes breast cancer cells invasion and metastasis via the AKT-GSK3-Snail pathway. Oncotarget. 2017; 8:13357–13366.
Not in our library10.18632/oncotarget.14528
114.
Ye J., Wang J., Zhang N., Liu Y., Tan L., Xu L. Expression of TARBP1 protein in human non-small-cell lung cancer and its prognostic significance. Oncol. Lett.2018; 15:7182–7190.
Not in our library10.3892/ol.2018.8202
115.
Sand M., Skrygan M., Georgas D., Arenz C., Gambichler T., Sand D., Altmeyer P., Bechara F.G. Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer. Mol. Carcinog.2012; 51:916–922.
Not in our library10.1002/mc.20861
116.
Kato T., Daigo Y., Hayama S., Ishikawa N., Yamabuki T., Ito T., Miyamoto M., Kondo S., Nakamura Y. A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis. Cancer Res.2005; 65:5638–5646.
Not in our library10.1158/0008-5472.can-05-0600
117.
Bykhovskaya Y., Casas K., Mengesha E., Inbal A., Fischel-Ghodsian N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet.2004; 74:1303–1308.
Not in our library10.1086/421530
118.
Gatza M.L., Silva G.O., Parker J.S., Fan C., Perou C.M. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat. Genet.2014; 46:1051–1059.
Not in our library10.1038/ng.3073
119.
Tan X.-L., Moyer A.M., Fridley B.L., Schaid D.J., Niu N., Batzler A.J., Jenkins G.D., Abo R.P., Li L., Cunningham J.M. et al. Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy. Clin. Cancer Res.2011; 17:5801–5811.
Not in our library10.1158/1078-0432.ccr-11-1133
120.
Alazami A.M., Hijazi H., Al-Dosari M.S., Shaheen R., Hashem A., Aldahmesh M.A., Mohamed J.Y., Kentab A., Salih M.A., Awaji A. et al. Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus. J. Med. Genet.2013; 50:425–430.
Not in our library10.1136/jmedgenet-2012-101378
121.
Frye M., Watt F.M. The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Curr. Biol.2006; 16:971–981.
Not in our library10.1016/j.cub.2006.04.027
122.
Guy M.P., Shaw M., Weiner C.L., Hobson L., Stark Z., Rose K., Kalscheuer V.M., Gecz J., Phizicky E.M. Defects in tRNA anticodon loop 2′-O-methylation are implicated in nonsyndromic X-linked intellectual disability due to mutations in FTSJ1. Hum. Mutat.2015; 36:1176–1187.
Not in our library10.1002/humu.22897
123.
Wang R., Lei T., Fu F., Li R., Jing X., Yang X., Liu J., Li D., Liao C. Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China. Pediatr. Neonatol.2018; S1875-9572:30317–30320.
Not in our library10.1016/j.pedneo.2018.03.006
124.
Xie X., Wang Z., Chen Y. Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction. Mol. Cell. Biochem.2007; 301:115–122.
Not in our library10.1007/s11010-006-9402-5
125.
Gündüz U., Elliott M.S., Seubert P.H., Houghton J.A., Houghton P.J., Trewyn R.W., Katze J.R. Absence of tRNA-guanine transglycosylase in a human colon adenocarcinoma cell line. Biochim. Biophys. Acta. 1992; 1139:229–238.
Not in our library10.1016/0925-4439(92)90139-e
126.
Slaugenhaupt S.A., Blumenfeld A., Gill S.P., Leyne M., Mull J., Cuajungco M.P., Liebert C.B., Chadwick B., Idelson M., Reznik L. et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet.2001; 68:598–605.
Not in our library10.1086/318810
127.
Rapino F., Delaunay S., Rambow F., Zhou Z., Tharun L., De Tullio P., Sin O., Shostak K., Schmitz S., Piepers J. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature. 2018; 558:605–609.
Not in our library10.1038/s41586-018-0243-7
128.
Addis L., Ahn J.W., Dobson R., Dixit A., Ogilvie C.M., Pinto D., Vaags A.K., Coon H., Chaste P., Wilson S. et al. Microdeletions of ELP4 are associated with language impairment, autism spectrum disorder, and mental retardation. Hum. Mutat.2015; 36:842–850.
Not in our library10.1002/humu.22816
129.
Fadason T., Ekblad C., Ingram J.R., Schierding W.S., O’Sullivan J.M. Physical interactions and expression quantitative traits loci identify regulatory connections for obesity and type 2 diabetes associated SNPs. Front. Genet.2017; 8:150.
Not in our library10.3389/fgene.2017.00150
130.
Delaunay S., Rapino F., Tharun L., Zhou Z., Heukamp L., Termathe M., Shostak K., Klevernic I., Florin A., Desmecht H. et al. Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer. J. Exp. Med.2016; 213:2503–2523.
Not in our library10.1084/jem.20160397
131.
Loss of a Conserved tRNA Anticodon Modification Perturbs Cellular Signaling · 2013
No notice
132.
Shaheen R., Patel N., Shamseldin H., Alzahrani F., Al-Yamany R., ALMoisheer A., Ewida N., Anazi S., Alnemer M., Elsheikh M. et al. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet. Med.2016; 18:686–695.
Not in our library10.1038/gim.2015.147
133.
Shaheen R., Al-Salam Z., El-Hattab A.W., Alkuraya F.S. The syndrome dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): Report of two additional patients. Am. J. Med. Genet. A. 2016; 170:3222–3226.
Not in our library10.1002/ajmg.a.37877
134.
Yamada Y., Yasukochi Y., Kato K., Oguri M., Horibe H., Fujimaki T., Takeuchi I., Sakuma J. Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population. Biomed. Rep.2018; 9:383–404.
Not in our library10.3892/br.2018.1152
135.
Powell C.A., Kopajtich R., D’Souza A.R., Rorbach J., Kremer L.S., Husain R.A., Dallabona C., Donnini C., Alston C.L., Griffin H. et al. TRMT5 mutations cause a defect in Post-transcriptional modification of mitochondrial tRNA associated with multiple Respiratory-Chain deficiencies. Am. J. Hum. Genet.2015; 97:319–328.
Not in our library10.1016/j.ajhg.2015.06.011
136.
Zhou M., Xue L., Chen Y., Li H., He Q., Wang B., Meng F., Wang M., Guan M.-X. A hypertension-associated mitochondrial DNA mutation introduces an m1G37 modification into tRNAMet, altering its structure and function. J. Biol. Chem.2018; 293:1425–1438.
Not in our library10.1074/jbc.ra117.000317
137.
Rodriguez V., Chen Y., Elkahloun A., Dutra A., Pak E., Chandrasekharappa S. Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer. Genes. Chromosomes Cancer. 2007; 46:694–707.
Not in our library10.1002/gcc.20454
138.
Simpson H.M., Khan R.Z., Song C., Sharma D., Sadashivaiah K., Furusawa A., Liu X., Nagaraj S., Sengamalay N., Sadzewicz L. et al. Concurrent mutations in ATM and genes associated with common γ chain signaling in peripheral T cell lymphoma. PLoS One. 2015; 10:e0141906.
Not in our library10.1371/journal.pone.0141906
139.
Yeon S.Y., Jo Y.S., Choi E.J., Kim M.S., Yoo N.J., Lee S.H. Frameshift mutations in repeat sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 genes in colon cancers. Pathol. Oncol. Res.2018; 24:617–622.
Not in our library10.1007/s12253-017-0287-2
140.
Huang B., Zhai W., Hu G., Huang C., Xie T., Zhang J., Xu Y. MicroRNA-206 acts as a tumor suppressor in bladder cancer via targeting YRDC. Am. J. Transl. Res.2016; 8:4705–4715.
Not in our library
141.
Hyun H.S., Kim S.H., Park E., Cho M.H., Kang H.G., Lee H.S., Miyake N., Matsumoto N., Tsukaguchi H., Cheong H. Il A familial case of Galloway-Mowat syndrome due to a novel TP53RK mutation: a case report. BMC Med. Genet.2018; 19:131.
Not in our library10.1186/s12881-018-0649-y
142.
Hideshima T., Cottini F., Nozawa Y., Seo H.-S., Ohguchi H., Samur M.K., Cirstea D., Mimura N., Iwasawa Y., Richardson P.G. et al. p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood. 2017; 129:1308–1319.
Not in our library10.1182/blood-2016-09-738500
143.
tRNA Methyltransferase Homolog Gene TRMT10A Mutation in Young Onset Diabetes and Primary Microcephaly in Humans · 2013
No notice
144.
Ismail N.A., Ragab S., Abd El Dayem S.M., Baky A.N.A.E., Hamed M., Ahmed Kamel S., Adel El Halim D. Implication of CDKAL1 single-nucleotide polymorphism rs 9465871 in obese and non-obese Egyptian children. Med. J. Malaysia. 2018; 73:286–290.
Not in our library
145.
Yang X.-X., He X.-Q., Li F.-X., Wu Y.-S., Gao Y., Li M. Risk-association of DNA methyltransferases polymorphisms with gastric cancer in the Southern Chinese population. Int. J. Mol. Sci.2012; 13:8364–8378.
Not in our library10.3390/ijms13078364
146.
Chowdhury S., Hobbs C.A., MacLeod S.L., Cleves M.A., Melnyk S., James S.J., Hu P., Erickson S.W. Associations between maternal genotypes and metabolites implicated in congenital heart defects. Mol. Genet. Metab.2012; 107:596–604.
Not in our library10.1016/j.ymgme.2012.09.022
147.
Shaheen R., Han L., Faqeih E., Ewida N., Alobeid E., Phizicky E.M., Alkuraya F.S. A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Hum. Genet.2016; 135:707–713.
Not in our library10.1007/s00439-016-1665-7
148.
Abdelrahman H.A., Al-Shamsi A.M., Ali B.R., Al-Gazali L. A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease. Clin. Genet.2018; 94:586–587.
Not in our library10.1111/cge.13443
149.
Leschziner G.D., Coffey A.J., Andrew T., Gregorio S.P., Dias-Neto E., Calafato M., Bentley D.R., Kinton L., Sander J.W., Johnson M.R. Q8IYL2 is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS). Epilepsy Res.2011; 96:109–115.
Not in our library10.1016/j.eplepsyres.2011.05.010
150.
Hadjigeorgiou G.M., Kountra P.-M., Koutsis G., Tsimourtou V., Siokas V., Dardioti M., Rikos D., Marogianni C., Aloizou A.-M., Karadima G. et al. Replication study of GWAS risk loci in Greek multiple sclerosis patients. Neurol. Sci.2018; doi:10.1007/s10072-018-3617-6.
Not in our library10.1007/s10072-018-3617-6
151.
Mutation in WDR4 impairs tRNA m7G46 methylation and causes a distinct form of microcephalic primordial dwarfism · 2015
No notice
152.
Hicks D.G., Janarthanan B.R., Vardarajan R., Kulkarni S.A., Khoury T., Dim D., Budd G.T., Yoder B.J., Tubbs R., Schreeder M.T. et al. The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence. BMC Cancer. 2010; 10:108.
Not in our library10.1186/1471-2407-10-108
153.
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease · 2011
No notice
154.
Shi L., Yang X.-M., Tang D.-D., Liu G., Yuan P., Yang Y., Chang L.-S., Zhang L.-R., Song D.-K. Expression and significance of m1A transmethylase, hTrm6p/hTrm61p and its related gene hTrm6/hTrm61 in bladder urothelial carcinoma. Am. J. Cancer Res.2015; 5:2169–2179.
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155.
Macari F., El-Houfi Y., Boldina G., Xu H., Khoury-Hanna S., Ollier J., Yazdani L., Zheng G., Bièche I., Legrand N. et al. TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis. Oncogene. 2016; 35:1785–1796.
Not in our library10.1038/onc.2015.244
156.
Li C., Wang S., Xing Z., Lin A., Liang K., Song J., Hu Q., Yao J., Chen Z., Park P.K. et al. A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis. Nat. Cell Biol.2017; 19:106–119.
Not in our library10.1038/ncb3464
157.
Metodiev M.D., Thompson K., Alston C.L., Morris A.A.M., He L., Assouline Z., Rio M., Bahi-Buisson N., Pyle A., Griffin H. et al. Recessive mutations in TRMT10C cause defects in mitochondrial RNA processing and multiple respiratory chain deficiencies. Am. J. Hum. Genet.2016; 98:993–1000.
Not in our library10.1016/j.ajhg.2016.03.010
158.
Oerum S., Roovers M., Leichsenring M., Acquaviva-Bourdain C., Beermann F., Gemperle-Britschgi C., Fouilhoux A., Korwitz-Reichelt A., Bailey H.J., Droogmans L. et al. Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein. Biochim. Biophys. Acta Mol. Basis Dis.2017; 1863:3294–3302.
Not in our library10.1016/j.bbadis.2017.09.002
159.
Blaesius K., Abbasi A.A., Tahir T.H., Tietze A., Picker-Minh S., Ali G., Farooq S., Hu H., Latif Z., Khan M.N. et al. Mutations in the tRNA methyltransferase 1 gene TRMT1 cause congenital microcephaly, isolated inferior vermian hypoplasia and cystic leukomalacia in addition to intellectual disability. Am. J. Med. Genet. A. 2018; 176:2517–2521.
Not in our library10.1002/ajmg.a.38631
160.
Job B., Bernheim A., Beau-Faller M., Camilleri-Broët S., Girard P., Hofman P., Mazières J., Toujani S., Lacroix L., Laffaire J. et al. Genomic aberrations in lung adenocarcinoma in never smokers. PLoS One. 2010; 5:e15145.
Not in our library10.1371/journal.pone.0015145
161.
RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia · 2018
Corrected
162.
Kopajtich R., Nicholls T.J., Rorbach J., Metodiev M.D., Freisinger P., Mandel H., Vanlander A., Ghezzi D., Carrozzo R., Taylor R.W. et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am. J. Hum. Genet.2014; 95:708–720.
Not in our library10.1016/j.ajhg.2014.10.017
163.
Bykhovskaya Y., Mengesha E., Wang D., Yang H., Estivill X., Shohat M., Fischel-Ghodsian N. Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3. Mol. Genet. Metab.2004; 83:199–206.
Not in our library10.1016/j.ymgme.2004.07.009
164.
Li X., Li R., Lin X., Guan M.-X. Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation. J. Biol. Chem.2002; 277:27256–27264.
Not in our library10.1074/jbc.m203267200
165.
Taylor R.W., Pyle A., Griffin H., Blakely E.L., Duff J., He L., Smertenko T., Alston C.L., Neeve V.C., Best A. et al. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014; 312:68–77.
Not in our library10.1001/jama.2014.7184
166.
Donner I., Katainen R., Kaasinen E., Aavikko M., Sipilä L.J., Pukkala E., Aaltonen L.A. Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma. Fam. Cancer. 2018; doi:10.1007/s10689-018-0099-x.
Not in our library10.1007/s10689-018-0099-x
167.
CO2-sensitive tRNA modification associated with human mitochondrial disease · 2018
No notice
168.
Kernohan K.D., Dyment D.A., Pupavac M., Cramer Z., McBride A., Bernard G., Straub I., Tetreault M., Hartley T., Huang L. et al. Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene. Hum. Mutat.2017; 38:511–516.
Not in our library10.1002/humu.23196
169.
Xiong J., Wang Y., Gu Y., Xue Y., Dang L., Li Y. CDK5RAP1 targeting NF-κB signaling pathway in human malignant melanoma A375 cell apoptosis. Oncol. Lett.2018; 15:4767–4774.
Not in our library10.3892/ol.2018.7920
170.
Khan M.A., Rafiq M.A., Noor A., Hussain S., Flores J. V, Rupp V., Vincent A.K., Malli R., Ali G., Khan F.S. et al. Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am. J. Hum. Genet.2012; 90:856–863.
Not in our library10.1016/j.ajhg.2012.03.023
171.
Frye M., Dragoni I., Chin S.-F., Spiteri I., Kurowski A., Provenzano E., Green A., Ellis I.O., Grimmer D., Teschendorff A. et al. Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancer. Cancer Lett.2010; 289:71–80.
Not in our library10.1016/j.canlet.2009.08.004
172.
Abbasi-Moheb L., Mertel S., Gonsior M., Nouri-Vahid L., Kahrizi K., Cirak S., Wieczorek D., Motazacker M.M., Esmaeeli-Nieh S., Cremer K. et al. Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am. J. Hum. Genet.2012; 90:847–855.
Not in our library10.1016/j.ajhg.2012.03.021
173.
Sekar S., McDonald J., Cuyugan L., Aldrich J., Kurdoglu A., Adkins J., Serrano G., Beach T.G., Craig D.W., Valla J. et al. Alzheimer's disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. Neurobiol. Aging. 2015; 36:583–591.
Not in our library10.1016/j.neurobiolaging.2014.09.027
174.
Couch F.J., Kuchenbaecker K.B., Michailidou K., Mendoza-Fandino G.A., Nord S., Lilyquist J., Olswold C., Hallberg E., Agata S., Ahsan H. et al. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nat. Commun.2016; 7:11375.
Not in our library10.1038/ncomms11375
175.
Shaheen R., Maddirevula S., Ewida N., Alsahli S., Abdel-Salam G.M.H., Zaki M.S., Tala S. Al, Alhashem A., Softah A., Al-Owain M. et al. Genomic and phenotypic delineation of congenital microcephaly. Genet. Med.2018; doi:10.1038/s41436-018-0140-3.
Not in our library10.1038/s41436-018-0140-3
176.
Edvardson S., Elbaz-Alon Y., Jalas C., Matlock A., Patel K., Labbé K., Shaag A., Jackman J.E., Elpeleg O. A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay. Neurogenetics. 2016; 17:219–225.
Not in our library10.1007/s10048-016-0487-z
177.
Yew T.W., McCreight L., Colclough K., Ellard S., Pearson E.R. tRNA methyltransferase homologue gene TRMT10A mutation in young adult-onset diabetes with intellectual disability, microcephaly and epilepsy. Diabet. Med.2016; 33:e21–e25.
Not in our library10.1111/dme.13024
178.
Zung A., Kori M., Burundukov E., Ben-Yosef T., Tatoor Y., Granot E. Homozygous deletion of TRMT10A as part of a contiguous gene deletion in a syndrome of failure to thrive, delayed puberty, intellectual disability and diabetes mellitus. Am. J. Med. Genet. A. 2015; 167A:3167–3173.
Not in our library10.1002/ajmg.a.37341
179.
Narayanan M., Ramsey K., Grebe T., Schrauwen I., Szelinger S., Huentelman M., Craig D., Narayanan V. C4RCD Research Group Case Report: Compound heterozygous nonsense mutations in TRMT10A are associated with microcephaly, delayed development, and periventricular white matter hyperintensities [version 1; referees: 2 approved]. F1000Research. 2015; 4:912.
Not in our library10.12688/f1000research.7106.1
180.
Gillis D., Krishnamohan A., Yaacov B., Shaag A., Jackman J.E., Elpeleg O. TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly. J. Med. Genet.2014; 51:581–586.
Not in our library10.1136/jmedgenet-2014-102282
181.
Zhang X., Liu J., Yan S., Huang K., Bai Y., Zheng S. High expression of N-acetyltransferase 10: a novel independent prognostic marker of worse outcome in patients with hepatocellular carcinoma. Int. J. Clin. Exp. Pathol.2015; 8:14765–14771.
Not in our library
182.
Ma R., Chen J., Jiang S., Lin S., Zhang X., Liang X. Up regulation of NAT10 promotes metastasis of hepatocellular carcinoma cells through epithelial-to-mesenchymal transition. Am. J. Transl. Res.2016; 8:4215–4223.
Not in our library
183.
Patton J.R., Bykhovskaya Y., Mengesha E., Bertolotto C., Fischel-Ghodsian N. Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. J. Biol. Chem.2005; 280:19823–19828.
Not in our library10.1074/jbc.m500216200
184.
Fernandez-Vizarra E., Berardinelli A., Valente L., Tiranti V., Zeviani M. Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). J. Med. Genet.2007; 44:173–180.
Not in our library10.1136/jmg.2006.045252
185.
El-Hattab A.W., Saleh M.A., Hashem A., Al-Owain M., Asmari A. Al, Rabei H., Abdelraouf H., Hashem M., Alazami A.M., Patel N. et al. ADAT3-related intellectual disability: Further delineation of the phenotype. Am. J. Med. Genet. A. 2016; 170A:1142–1147.
Not in our library10.1002/ajmg.a.37578
186.
Sharkia R., Zalan A., Jabareen-Masri A., Zahalka H., Mahajnah M. A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome. Eur. J. Med. Genet.2018; S1769-7212:30574–30583.
Not in our library10.1016/j.ejmg.2018.10.001
187.
Salehi Chaleshtori A.R., Miyake N., Ahmadvand M., Bashti O., Matsumoto N., Noruzinia M. A novel 8-bp duplication in ADAT3 causes mild intellectual disability. Hum. genome Var.2018; 5:7.
Not in our library10.1038/s41439-018-0007-9
188.
Bonnet C., Grégoire M.J., Brochet K., Raffo E., Leheup B., Jonveaux P. Pure de-novo 5 Mb duplication at Xp11.22-p11.23 in a male: phenotypic and molecular characterization. J. Hum. Genet.2006; 51:815–821.
Not in our library10.1007/s10038-006-0023-3
189.
Fahiminiya S., Almuriekhi M., Nawaz Z., Staffa A., Lepage P., Ali R., Hashim L., Schwartzentruber J., Abu Khadija K., Zaineddin S. et al. Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. Clin. Genet.2014; 86:134–141.
Not in our library10.1111/cge.12280
190.
Anderson S.L., Coli R., Daly I.W., Kichula E.A., Rork M.J., Volpi S.A., Ekstein J., Rubin B.Y. Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet.2001; 68:753–758.
Not in our library10.1086/318808
191.
Bento-Abreu A., Jager G., Swinnen B., Rué L., Hendrickx S., Jones A., Staats K.A., Taes I., Eykens C., Nonneman A. et al. Elongator subunit 3 (ELP3) modifies ALS through tRNA modification. Hum. Mol. Genet.2018; 27:1276–1289.
Not in our library10.1093/hmg/ddy043
192.
Ladang A., Rapino F., Heukamp L.C., Tharun L., Shostak K., Hermand D., Delaunay S., Klevernic I., Jiang Z., Jacques N. et al. Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med.2015; 212:2057–2075.
Not in our library10.1084/jem.20142288
193.
Belalcazar L.M., Papandonatos G.D., McCaffery J.M., Peter I., Pajewski N.M., Erar B., Allred N.D., Balasubramanyam A., Bowden D.W., Brautbar A. et al. A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes. Physiol. Genomics. 2015; 47:215–224.
Not in our library10.1152/physiolgenomics.00109.2014
194.
Close P., Gillard M., Ladang A., Jiang Z., Papuga J., Hawkes N., Nguyen L., Chapelle J.-P., Bouillenne F., Svejstrup J. et al. DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of Elongator. J. Biol. Chem.2012; 287:32535–32545.
Not in our library10.1074/jbc.m112.402727
195.
Braun D.A., Rao J., Mollet G., Schapiro D., Daugeron M.-C., Tan W., Gribouval O., Boyer O., Revy P., Jobst-Schwan T. et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat. Genet.2017; 49:1529–1538.
Not in our library10.1038/ng.3933
196.
Wang P.Z.T., Prasad C., Rodriguez Cuellar C.I., Filler G. Nephrological and urological complications of homozygous c.974G>A (p.Arg325Gln) OSGEP mutations. Pediatr. Nephrol.2018; 33:2201–2204.
Not in our library10.1007/s00467-018-4060-x
197.
Tang X., Hobbs C.A., Cleves M.A., Erickson S.W., MacLeod S.L., Malik S National Birth Defects Prevention Study Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use. Birth Defects Res. A. Clin. Mol. Teratol.2015; 103:834–842.
Not in our library10.1002/bdra.23370
198.
Park S., Liu M., Kang S. Alcohol Intake Interacts with CDKAL1, HHEX, and OAS3 genetic variants, associated with the risk of type 2 diabetes by lowering insulin secretion in Korean adults. Alcohol. Clin. Exp. Res.2018; 42:2326–2336.
Not in our library10.1111/acer.13888
199.
Nfor O.N., Wu M.-F., Lee C.-T., Wang L., Liu W.-H., Tantoh D.M., Hsu S.-Y., Lee K.-J., Ho C.-C., Debnath T. et al. Body mass index modulates the association between CDKAL1 rs10946398 variant and type 2 diabetes among Taiwanese women. Sci. Rep.2018; 8:13235.
Not in our library10.1038/s41598-018-31415-4
200.
Alcina A., Fedetz M., Fernández O., Saiz A., Izquierdo G., Lucas M., Leyva L., García-León J.-A., Abad-Grau M.D.M., Alloza I. et al. Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. J. Med. Genet.2013; 50:25–33.
Not in our library10.1136/jmedgenet-2012-101085
201.
Wikman H., Nymark P., Väyrynen A., Jarmalaite S., Kallioniemi A., Salmenkivi K., Vainio-Siukola K., Husgafvel-Pursiainen K., Knuutila S., Wolf M. et al. CDK4 is a probable target gene in a novel amplicon at 12q13.3-q14.1 in lung cancer. Genes. Chromosomes Cancer. 2005; 42:193–199.
Not in our library10.1002/gcc.20122
202.
Trimouille A., Lasseaux E., Barat P., Deiller C., Drunat S., Rooryck C., Arveiler B., Lacombe D. Further delineation of the phenotype caused by biallelic variants in the WDR4 gene. Clin. Genet.2018; 93:374–377.
Not in our library10.1111/cge.13074
203.
Chen X., Gao Y., Yang L., Wu B., Dong X., Liu B., Lu Y., Zhou W., Wang H. Speech and language delay in a patient with WDR4 mutations. Eur. J. Med. Genet.2018; 61:468–472.
Not in our library10.1016/j.ejmg.2018.03.007
204.
Braun D.A., Shril S., Sinha A., Schneider R., Tan W., Ashraf S., Hermle T., Jobst-Schwan T., Widmeier E., Majmundar A.J. et al. Mutations in WDR4 as a new cause of Galloway-Mowat syndrome. Am. J. Med. Genet. A. 2018; 176:2460–2465.
Not in our library10.1002/ajmg.a.40489
205.
Chen C.-P., Chern S.-R., Wu P.-S., Chen S.-W., Lai S.-T., Chuang T.-Y., Chen W.-L., Yang C.-W., Wang W. Prenatal diagnosis of a 3.2-Mb 2p16.1-p15 duplication associated with familial intellectual disability. Taiwan. J. Obstet. Gynecol.2018; 57:578–582.
Not in our library10.1016/j.tjog.2018.06.018
206.
Medrano L.M., Pascual V., Bodas A., López-Palacios N., Salazar I., Espino-Paisán L., González-Pérez B., Urcelay E., Mendoza J.L., Núñez C. Expression patterns common and unique to ulcerative colitis and celiac disease. Ann. Hum. Genet.2018; doi:10.1111/ahg.12293.
Not in our library10.1111/ahg.12293
207.
He X.-Y., Isaacs C., Yang S.-Y. Roles of mitochondrial 17β-Hydroxysteroid dehydrogenase type 10 in Alzheimer's disease. J. Alzheimers. Dis.2018; 62:665–673.
Not in our library10.3233/jad-170974
208.
Roussel E., Drolet M.-C., Lavigne A.-M., Arsenault M., Couet J. Multiple short-chain dehydrogenases/reductases are regulated in pathological cardiac hypertrophy. FEBS Open Biol.2018; 8:1624–1635.
Not in our library10.1002/2211-5463.12506
209.
Davarniya B., Hu H., Kahrizi K., Musante L., Fattahi Z., Hosseini M., Maqsoud F., Farajollahi R., Wienker T.F., Ropers H.H. et al. The role of a novel TRMT1 gene mutation and rare GRM1 gene defect in intellectual disability in two azeri families. PLoS One. 2015; 10:e0129631.
Not in our library10.1371/journal.pone.0129631
210.
Najmabadi H., Hu H., Garshasbi M., Zemojtel T., Abedini S.S., Chen W., Hosseini M., Behjati F., Haas S., Jamali P. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011; 478:57–63.
Not in our library10.1038/nature10423
211.
Meseguer S., Martínez-Zamora A., García-Arumí E., Andreu A.L., Armengod M.-E. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum. Mol. Genet.2015; 24:167–184.
Not in our library10.1093/hmg/ddu427
212.
Li X., Guan M.-X. A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness-associated mitochondrial 12S rRNA mutation. Mol. Cell. Biol.2002; 22:7701–7711.
Not in our library10.1128/mcb.22.21.7701-7711.2002
213.
Murayama K., Shimura M., Liu Z., Okazaki Y., Ohtake A. Recent topics: the diagnosis, molecular genesis, and treatment of mitochondrial diseases. J. Hum. Genet.2018; 64:113–125.
Not in our library10.1038/s10038-018-0528-6
214.
Asano K., Suzuki T., Saito A., Wei F.-Y., Ikeuchi Y., Numata T., Tanaka R., Yamane Y., Yamamoto T., Goto T. et al. Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease. Nucleic Acids Res.2018; 46:1565–1583.
Not in our library10.1093/nar/gky068
215.
Kim T.W., Kim B., Kim J.H., Kang S., Park S.-B., Jeong G., Kang H.-S., Kim S.J. Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer. BMC Cancer. 2013; 13:502.
Not in our library10.1186/1471-2407-13-502
216.
Ghezzi D., Baruffini E., Haack T.B., Invernizzi F., Melchionda L., Dallabona C., Strom T.M., Parini R., Burlina A.B., Meitinger T. et al. Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. Am. J. Hum. Genet.2012; 90:1079–1087.
Not in our library10.1016/j.ajhg.2012.04.011
217.
Umeda N., Suzuki T., Yukawa M., Ohya Y., Shindo H., Watanabe K., Suzuki T. Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J. Biol. Chem.2005; 280:1613–1624.
Not in our library10.1074/jbc.m409306200
218.
Gaignard P., Gonzales E., Ackermann O., Labrune P., Correia I., Therond P., Jacquemin E., Slama A. Mitochondrial infantile liver disease due to TRMU gene Mutations: Three new cases. JIMD Rep.2013; 11:117–123.
Not in our library10.1007/8904_2013_230
219.
Schara U., von Kleist-Retzow J.-C., Lainka E., Gerner P., Pyle A., Smith P.M., Lochmüller H., Czermin B., Abicht A., Holinski-Feder E. et al. Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. J. Inherit. Metab. Dis.2011; 34:197–201.
Not in our library10.1007/s10545-010-9250-z
220.
Zeharia A., Shaag A., Pappo O., Mager-Heckel A.-M., Saada A., Beinat M., Karicheva O., Mandel H., Ofek N., Segel R. et al. Acute infantile liver failure due to mutations in the TRMU gene. Am. J. Hum. Genet.2009; 85:401–407.
Not in our library10.1016/j.ajhg.2009.08.004
221.
Guan M.-X., Yan Q., Li X., Bykhovskaya Y., Gallo-Teran J., Hajek P., Umeda N., Zhao H., Garrido G., Mengesha E. et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am. J. Hum. Genet.2006; 79:291–302.
Not in our library10.1086/506389
222.
Khatami S., Rokni-Zadeh H., Mohsen-Pour N., Biglari A., Changi-Ashtiani M., Shahrooei M., Shahani T. Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss. Mitochondrion. 2018; S1567-7249:30024–30032.
Not in our library10.1016/j.mito.2018.08.006
223.
Yue Z., Li H.-T., Yang Y., Hussain S., Zheng C.-H., Xia J., Chen Y. Identification of breast cancer candidate genes using gene co-expression and protein-protein interaction information. Oncotarget. 2016; 7:36092–36100.
Not in our library10.18632/oncotarget.9132
224.
Chen S., Zheng Z., Tang J., Lin X., Wang X., Lin J. Association of polymorphisms and haplotype in the region of TRIT1, MYCL1 and MFSD2A with the risk and clinicopathological features of gastric cancer in a southeast Chinese population. Carcinogenesis. 2013; 34:1018–1024.
Not in our library10.1093/carcin/bgt010
225.
Spinola M., Galvan A., Pignatiello C., Conti B., Pastorino U., Nicander B., Paroni R., Dragani T.A. Identification and functional characterization of the candidate tumor suppressor gene TRIT1 in human lung cancer. Oncogene. 2005; 24:5502–5509.
Not in our library10.1038/sj.onc.1208687
226.
Palmer C.J., Bruckner R.J., Paulo J.A., Kazak L., Long J.Z., Mina A.I., Deng Z., LeClair K.B., Hall J.A., Hong S. et al. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol. Metab.2017; 6:1212–1225.
Not in our library10.1016/j.molmet.2017.07.013
227.
Shin M.-K., Uhm Y.-K., Lee J.-H., Kim S.-K., Chung J.-H., Lee M.-H. Association between CDK5RAP1 polymorphisms and susceptibility to vitiligo in the Korean population. Eur. J. Dermatol.22:495–499.
Not in our library10.1684/ejd.2012.1728
228.
Steinthorsdottir V., Thorleifsson G., Reynisdottir I., Benediktsson R., Jonsdottir T., Walters G.B., Styrkarsdottir U., Gretarsdottir S., Emilsson V., Ghosh S. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet.2007; 39:770–775.
Not in our library10.1038/ng2043
229.
Okamoto M., Hirata S., Sato S., Koga S., Fujii M., Qi G., Ogawa I., Takata T., Shimamoto F., Tatsuka M. Frequent increased gene copy number and high protein expression of tRNA (cytosine-5-)-methyltransferase (NSUN2) in human cancers. DNA Cell Biol.2012; 31:660–671.
Not in our library10.1089/dna.2011.1446
230.
Martinez F.J., Lee J.H., Lee J.E., Blanco S., Nickerson E., Gabriel S., Frye M., Al-Gazali L., Gleeson J.G. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J. Med. Genet.2012; 49:380–385.
Not in our library10.1136/jmedgenet-2011-100686
231.
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Not in our library10.1007/s12031-015-0592-8
232.
Yi J., Gao R., Chen Y., Yang Z., Han P., Zhang H., Dou Y., Liu W., Wang W., Du G. et al. Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer. Oncotarget. 2017; 8:20751–20765.
Not in our library10.18632/oncotarget.10612

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MODOMICS: a database of RNA modification pathways. 2021 update · 2021
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