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The Centromere: Chromatin Foundation for the Kinetochore Machinery

Tatsuo Fukagawa, William C. Earnshaw

Developmental Cell · 2014 · Review · CC BY

doi:10.1016/j.devcel.2014.08.016

Abstract

Since discovery of the centromere-specific histone H3 variant CENP-A, centromeres have come to be defined as chromatin structures that establish the assembly site for the complex kinetochore machinery. In most organisms, centromere activity is defined epigenetically, rather than by specific DNA sequences. In this review, we describe selected classic work and recent progress in studies of centromeric chromatin with a focus on vertebrates. We consider possible roles for repetitive DNA sequences found at most centromeres, chromatin factors and modifications that assemble and activate CENP-A chromatin for kinetochore assembly, plus the use of artificial chromosomes and kinetochores to study centromere function.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

In the 1930s, the site where chromosomes associate with the spindle during cell division was independently given two names: the “centromere” and the “kinetochore”. The terms were long thought redundant, but it has recently proven useful to differentiate between them.

Centromeres, classically defined in genetics as regions of suppressed meiotic recombination, were later recognized as the primary constriction of mitotic chromosomes. Centromeres are enriched in satellite repeats that stain dark by C-banding. When electron microscopy revealed a multilayered structure that binds to microtubules at the surface of centromeres, that structure was termed the “kinetochore.” The centromere is now generally accepted to be a chromatin structure that specifies where the kinetochore will form. Kinetochores are complex protein structures lacking DNA.

Molecular studies of the centromere/kinetochore began with the discovery that some patients with scleroderma spectrum disease (e.g., CREST syndrome) have anti-centromere autoantibodies (ACA). Three antigens, CENP-A, CENP-B, and CENP-C, are recognized by those sera. CENP-A is a centromere-specific histone H3 variant. CENP-A and CENP-C localize to the inner kinetochore. CENP-B is an α-satellite (human centromeric DNA)-binding protein. To date, over 100 kinetochore components have been identified. Aspects of kinetochore function that are beginning to be well understood include microtubule binding, chromosome movement, and checkpoint signaling. (For reviews, see,,,,, ).

The organization and functions of centromeric chromatin remain less understood subjects of active study. In this review, we discuss recent progress in understanding the organization, composition, and assembly of centromeric chromatin and DNA.

Point and Regional Centromeres of Model Organisms

Budding yeast Saccharomyces cerevisiae centromeres occupy a ∼125 bp DNA sequence, now termed a “point centromere”. They include three conserved DNA elements (CDE), CDEI, CDEII, and CDEIII that form a single nucleosome containing CENP-A (Cse4 in S. cerevisiae). The CDEI-III sequences are necessary and sufficient for active centromere formation, and a single base mutation in CDEIII can abolish centromere function.

Centromeres of the fission yeast Schizosaccharomyces pombe encompass 40–100 kb containing a central core (cnt) of 4–7 kb, where the kinetochore forms, flanked by repeated sequences (otr) that form heterochromatin. This configuration is known as a “regional centromere”. Both cnt and otr sequences are required for centromere function. Heterochromatin is required during de novo centromere formation. Transcription of otr and subsequent transcript processing by the RNAi machinery direct formation of pericentromeric heterochromatin.

Regional centromeres of the pathogenic yeast Candida albicans map to unique sequences of ∼3 kb on each of the 8 chromosomes. Although a truncated minichromosome containing a fragment from the centromere retained centromere activity, centromeric activity was not reconstituted when naked minichromosome DNA was introduced back into yeast. It was suggested that an unusual chromatin structure detected at endogenous centromeres might be involved in epigenetic specification of the centromere in this yeast.

The regional centromere is the most common organization for centromeres in humans and most model organisms characterized to date, including Neurospora crassa, Arabidopsis thaliana, Drosophila melanogaster, and Oryza sativa (rice). Common features of regional centromeres include the lack of a “magic” DNA sequence, the presence of complex repeated DNAs (satellite repeats together with centromeric retrotransposons), and an involvement of some sort of epigenetic mechanism in specification of the site for kinetochore assembly.

Nematodes, some insects, and plants assemble a “holocentromere” (originally, a holokinetochore) that extends along the entire length of the chromosome. Recent chromatin immunoprecipitation-on-chip (ChIP-chip) analyses in Caenorhabditis elegans revealed that CENP-A occupies nonrepeated regions of 10–12 kb dispersed across about half of the genome and is excluded from loci that are transcribed in the germline and early embryo (for a contrasting view, see ). Holocentromeres may consist of numerous CENP-A “seeds” dispersed along the chromosome that somehow cooperate to direct assembly of a functional kinetochore.

Kinetochores Assemble on Repetitive DNA Sequences in Most Organisms

In situ hybridization first revealed that satellite repeats were located at centromeres of mouse chromosomes. Subsequent studies identified human centromeric DNA as α-satellite. This DNA, with its 171 bp consensus sequence, exhibits a complex higher-order repeat (HOR) pattern, in which adjacent monomers may share no more than 50% sequence identity, but corresponding monomers among the HORs share >90% identity. Different-sized HORs are observed on differing human chromosomes, where they typically create a chromosome-specific array that spans 0.3–5 Mb within the centromere (Figure 1).

Sequence assembly across α-satellite arrays at human centromeres is difficult due to high sequence similarities within the arrays and variability between individuals. To date, complete maps across the HOR and into pericentromeric heterochromatin are available only for chromosomes 8, X, and Y. On the X, a repeating HOR structure is flanked by divergent α-satellite monomers not ordered into HOR (Figure 1). The functional kinetochore assembles on the HOR core, with monomeric α-satellite sequences comprising pericentromeric heterochromatin.

The conservation of α-satellite sequences at all natural human centromeres suggested that these HORs are required for centromere identity or function. However, this was ruled out by the discovery of human dicentric chromosomes containing α-satellite DNA arrays that do not nucleate kinetochore formation and functional neocentromeres lacking α-satellite sequences.

Thus, although there are exceptions (see below), centromere regions from most organisms contain repetitive sequences, suggesting that those sequences contribute to important aspects of centromere function.

Repetitive Sequences in Centromeres May Allow Kinetochore Plasticity

If kinetochores can form on nonrepetitive sequences, why do most centromeres contain repetitive sequences? One possibility is that repetitive sequences direct the formation of pericentromeric heterochromatin, with its molecular signature of heterochromatin protein 1 (HP1) bound to histone H3 trimethylated on lysine 9 (H3K9me3) (Figure 1). Although neocentromeres assembled on nonrepetitive DNA lack heterochromatin and yet function perfectly well in mitosis and meiosis, pericentromeric heterochromatin, which consists of unordered monomer units of α-satellite in human, appears to provide a boundary between the kinetochore and flanking euchromatin regions in natural centromeres and might act as a barrier to centromere migration (Figure 1).

Pericentromeric heterochromatin recruits cohesin, and centromeric cohesion is particularly important in meiosis I where sister chromatids must remain paired. A requirement for strong centromeric cohesion in meiosis I could select for the accumulation of repetitive sequences in centromeres over evolutionary time scales.

In humans, the CENP-A associated domain at natural centromeres varies between 200 and 2,000 kb on different chromosomes and individuals. Thus, kinetochores form only over a portion of the α-satellite arrays (Figure 1). Due to the repetitive nature of the underlying DNA at natural centromeres, the kinetochore region cannot be mapped unambiguously by modern ChIP methods. This can be done at human neocentromeres, where the CENP-A domain spans just 80–100 kb. Thus, neocentromeres are much smaller than native centromeres.

Although active genes are present within rice centromeres, kinetochore formation across a transcribed gene strongly suppressed transcription of that gene on the chicken Z chromosome. Thus, kinetochore formation on essential genes would be expected to be deleterious. Because regional centromere position is not strictly specified by DNA sequence, it is possible that the kinetochore position on the underlying DNA might drift slightly (Figure 2). In this case, repetitive arrays could provide a safety buffer within which such drift would be harmless (Figure 2). It will be interesting in future studies of unique sequence centromeres to test whether kinetochore position is fixed or plastic.

Neocentromeres Reveal Insights into Centromere Specification

Very rarely, disruption or inactivation of a natural centromere is followed by formation of a neocentromere at a new locus on a chromosome arm. Over 100 neocentromeres have been described in human clinical samples. They form on diverse DNA sequences and are not associated with α-satellite arrays, thus providing strong evidence that human centromeres are specified by sequence-independent epigenetic mechanisms.

Experimental generation of neocentromeres in model organisms has yielded insights into the process of neocentromere formation. In D. melanogaster, neocentromeres obtained following γ-irradiation-based chromosome breakage formed near the pericentromeric region of the X chromosome. Subsequently, neocentromeres were generated in S. pombe and C. albicans following targeted deletion of the original centromere and genetic selection for retention of the chromosome (Figure 3). C. albicans neocentromeres formed either in transcriptionally active or intergenic regions near the natural centromeres. In contrast, S. pombe neocentromeres preferentially formed near telomeric heterochromatin and efficient neocentromere formation required heterochromatin proteins.

Recently, chromosome engineering has allowed the efficient isolation of neocentromeres in chicken DT40 cells. Conditional deletion of the centromeres of chromosome Z or 5 led to neocentromere formation at a frequency of ∼3 × 10−6 on a wide range of both transcriptionally active and inactive sequences (Figure 3). Thus, neocentromeres can be “seeded” on either transcriptionally active or inactive regions of the genome, and heterochromatin is not required for centromere formation. However, neocentromere formation caused a significant drop in gene transcription when a neocentromere formed on an actively transcribed gene on the Z chromosome.

Chicken neocentromeres have a remarkably constant size of ∼40 ± 6 kb, and CENP-A domains did not expand even in cells overexpressing CENP-A. In contrast, increased levels of CENP-A expression human cells resulted in increased CENP-A incorporation at centromeres. CENP-A levels are regulated by a ubiquitin-dependent pathway in yeasts, and the mechanisms governing centromere size may vary.

Drosophila, barley, Candida, and chicken neocentromeres all formed close to the natural centromeres (Figure 3). Possibly, patterns of neocentromere formation are determined by noncentromeric incorporation of CENP-A (Figure 3) in regions with high histone turnover. Remarkably, significant levels of CENP-A in vertebrates are incorporated into chromatin at noncentromeric sites (30% in chicken and 74% in human RPE1 cells). Importantly, given the size of human genome, this still corresponds to a ∼50× concentration increase at centromeres. In chicken, the ectopic CENP-A is enriched in chromatin flanking the natural centromeres (the “CENP-A cloud”). Noncentromeric Cse4 (CENP-A) is also observed in budding yeast and might form a CENP-A “cloud” (Kerry Bloom, personal communication). The “cloud” was not detected in Candida, where it was proposed that neocentromeres might form in a CENP-A-rich zone created by specific three-dimensional packaging of the genome in nuclei.

We suggest that the ectopic “CENP-A cloud” functions to seed neocentromere formation when natural centromeres are disrupted (Figure 3). How centromere formation is suppressed in the ectopic “CENP-A cloud” and how this suppression is lifted once natural centromeres are compromised remain interesting questions for further study.

Nonrepetitive Centromeres Found in Horses, Orangutans, and Chickens

Sequencing the horse genome revealed that the centromere of chromosome 11 lacked repetitive sequences. The CENP-A domain of horse centromere 11 is ∼90 kb, similar to a typical human neocentromere (80–100 kb). Chickens also have nonrepetitive centromeres on chromosomes 5, 27, and Z (the others are repetitive). These nonrepetitive centromeres are only ∼40kb long based on CENP-A ChIP-seq analysis. Interestingly, orangutans also have one nonrepetitive centromere.

These nonrepeated centromeres might be evolutionally new centromeres (ENCs) that formed initially as neocentromeres, then become fixed in the population. It appears that over time, ENCs acquire repetitive DNA elements—presumably to stabilize them as proposed above.

Human Artificial Chromosomes and Epigenetic Engineering of Centromeric Chromatin

Given the powerful insights obtained by formation of artificial chromosomes in yeasts, it was thought that formation of artificial chromosomes in human cells might lead to important insights into centromere structure and function. The first human artificial chromosomes (HACs, also known as MACs or mammalian artificial chromosomes) were formed in cells transfected with a DNA cocktail including an α-satellite array, genomic DNA, and telomeric sequences. Subsequently, it was reported that yeast artificial chromosomes containing α-satellite DNA and retrofitted with telomeres could also form HACs. Circular BACs lacking telomeric sequences also give rise to stable HACs and are easier to construct.

A number of general principles emerged from these studies. Only α-satellite DNA with a regular HOR repeat structure and with CENP-B binding sites is functional for HAC formation. This was paradoxical as CENP-B knockout mice are viable and fertile. Subsequent studies revealed that CENP-B appears to manage heterochromatin formation during de novo centromere formation, and it also appears to be required for efficient recruitment of CENP-C to kinetochores (Daniele Fachinetti and Don Cleveland, personal communication). Interestingly, either excessive heterochromatin or excessive transcription flanking the α-satellite DNA sequences interferes with de novo centromere formation.

HACs have thus far proved to be of only limited utility in understanding the mechanisms of human centromere formation. HACs are observed only after multiple generations in cell culture during which an unknown sequence of events has occurred. HACs identified to date are considerably larger than the input DNA, and physical characterization of one HAC revealed that it had undergone a complex set of rearrangements and acquired sequences from the arm of chromosome 13.

Despite these limitations, the alphoidtetO HAC has recently begun to yield insights about the chromatin environment required within centromeric DNA in and around the kinetochore (Figure 4). When tetracycline repressor fusion proteins were used to direct various chromatin modifiers into the centromeric chromatin, this revealed that excessive heterochromatin or excessive transcriptional activity within the centromere are incompatible with kinetochore assembly and propagation. Interestingly, a moderate (10×) activation of transcription within the centromere is tolerated (Figure 4). Consistent with these results, transcription and RNA polymerase have been detected in centromeric sequences, even in mitotic cells. It thus appears that kinetochore stability at human centromeres requires finely balanced RNA transcription within an otherwise silent chromatin environment.

Are CENP-A-Containing Nucleosomes Different from Bulk Nucleosomes?

Centromeric chromatin forms a specialized structure in budding and fission yeasts. CENP-A sequences from model organisms have highly variable N-terminal tails, but in human cells, centromere targeting is directed by the 22 amino acid (aa) CENP-A targeting domain (CATD) located in the histone-fold region. The CATD binds the CENP-A-specific chaperone HJURP. The CENP-A nucleosome core is rigid, but overall the DNA wraps less tightly in both natural and neocentromeres than in conventional nucleosomes. These differences suggest that CENP-A nucleosomes are distinct from canonical H3 nucleosomes. Indeed, conflicting models have been proposed for the structure of CENP-A-containing nucleosomes, and a spirited ongoing controversy concerns whether they are octameric or tetrameric.

Octameric CENP-A nucleosomes can be reconstituted with recombinant histones and CENP-A-containing nucleosomes purified from human cells contained stoichiometric CENP-A, H4, H2A, and H2B, with two CENP-A molecules per nucleosome. X-ray crystallography revealed that the structure of reconstituted CENP-A nucleosomes resembles canonical nucleosomes with subtle differences.

In contrast, Henikoff and Dalal argued that CENP-A nucleosomes form a tetrameric hemisome containing a single copy of CENP-A, H4, H2A, and H2B in Drosophila cells. They also proposed that DNA wraps around CENP-A hemisomes with a handedness opposite to that found in canonical nucleosomes. Using atomic force microscopy (AFM), they suggested that CENP-A nucleosomes are half the height of canonical nucleosomes. More recently, studies in human cells and budding yeast proposed that the CENP-A-containing nucleosomes are dynamic, oscillating between octameric and tetrameric forms during cell-cycle progression.

Although this debate is still active, recent crosslinking, photobleaching, and AFM experiments suggest that most CENP-A-containing nucleosomes are octameric, with a more rigid core than canonical nucleosomes. A recent study using fully functional Cse4 with an internal tdEos tag after Leu81 in the N-terminal region showed clearly that budding yeast kinetochores have two copies of Cse4 in a single nucleosome. The authors also demonstrated that studies in which Cse4 copy number appeared to vary across the cell cycle can be explained by delays in the activation of fluorescent proteins.

This controversy appears to have a life of its own, and studies using isolated CENP-A nucleosomes could be confounded by the fact that many CENP-A nucleosomes are noncentromeric. However, although there is still no absolute consensus, most emerging data appear to support the existence of octameric CENP-A nucleosomes in vivo.

Even if CENP-A-containing nucleosomes are octameric, some of these could be heterotypic, with both CENP-A and H3. CENP-A/H3.3 heterotypic nucleosomes can indeed form following CENP-A overexpression, but this is mostly in noncentromere regions. Homotypic CENP-A/CENP-A nucleosomes predominate at centromeres.

How Are CENP-A Nucleosomes Distributed in Centromeres?

A critical question is how many CENP-A nucleosomes are required to define a kinetochore. Immunofluorescence on extended chromatin fibers, superresolution microscopy, and biochemical analyses all suggest that centromeres consist of islets of CENP-A nucleosomes interspersed between regions containing H3 nucleosomes (Figure 5). In S. cerevisiae, elegant biochemical and quantitative imaging experiments detected a single Cse4/CENP-A nucleosome in the point centromere. Other microscopy experiments suggest that other budding yeast strains might have up to three CENP-A nucleosomes per centromere. However, these are technically deceptively complex experiments.

Using S. cerevisiae as a standard (assuming a single CENP-A nucleosome per centromere), S. pombe centromeres were estimated to have 3 CENP-A nucleosomes and chicken DT40 cells to have 30. Because CENP-A associated regions are ∼5 kb (∼25 nucleosomes) in S. pombe and ∼40 kb (∼200 nucleosomes) in chicken, and assuming 200 bp per nucleosome, this suggests that one in six to eight centromeric nucleosomes contains CENP-A (Figure 5). Recent studies report larger numbers of CENP-A nucleosomes in S. pombe. A typical human neocentromere of 80–100 kb (400–500 nucleosomes) should contain ∼100 CENP-A nucleosomes (200 copies of CENP-A) per centromere (Figure 5). This is in remarkable agreement with the recent conclusion that human RPE1 cells have ∼100 CENP-A nucleosomes per mitotic kinetochore. Considering copy-number estimates for other kinetochore proteins and numbers of microtubules (10–20 per kinetochore), this value of 30–100 CENP-A nucleosomes per vertebrate kinetochore appears reasonable (Figure 5).

Folding of the CENP-A Chromatin Fiber at Centromeres

Analysis of extended centromeric chromatin fibers revealed that CENP-A forms clusters that alternate with chromatin containing canonical histone H3. The H3 nucleosomes carry the transcription-associated modification H3K4me2 and define a specialized class of chromatin termed “centrochromatin”. It was proposed that CENP-A was packaged either into an amphipathic-like solenoidal superhelix or as radial loops, with CENP-A nucleosomes clustered on the outer surface of the chromatin and H3 internal (Figure 5).

Two types of super-resolution microscopy combined to challenge this interpretation. High-resolution dual-label microscopy showed that CENP-T, an important linker between the chromatin and the outer kinetochore, was located significantly outside of CENP-A. PALM microscopy of unfolded fibers derived from chicken kinetochores found CENP-T in regions of H3 nucleosomes. In the amphipathic helix-loop model, this would place CENP-T on the inside, in direct contradiction with the dual-label microscopy mapping measurements.

To account for the superresolution mapping data, it was suggested that CENP-A chromatin might be organized as a sinusoidally folded patch, or boustrophedon, at the surface of the centromeric chromatin. The boustrophedon was proposed to be 4–5 layers deep (Figure 5), consistent with the 10 nm diameter of the nucleosome and the ∼60 nm thickness of the kinetochore plate typically observed in electron micrographs. Thus, the architecture of CENP-A chromatin and the boustrophedon model remains questions in need of further experimentation.

The Paradoxical Timing of CENP-A Incorporation into Centromeres

New CENP-A is incorporated into the centromere during early G1 phase in vertebrate cells, following the drop in mitosis-associated CDK activity. This was unexpected, because most canonical H3 is incorporated into chromatin during DNA replication. Furthermore, it means that cells traverse mitosis with only half of their maximal complement of CENP-A. This is not what one might have predicted given that centromeres perform their most important functions during mitosis.

Budding yeast Cse4 (CENP-A) is incorporated into centromeres during S-phase coupled with DNA replication and following the complete removal of preexisting Cse4. Thus CENP-A incorporation timing differs between yeast and vertebrates. In the latter, histone H3.3 incorporated into centromeres during S-phase might function as a placeholder for new CENP-A deposition in the next G1.

Genetic analysis in S. pombe identified Mis16 and Mis18 as factors involved in CENP-A localization. Mis16 is the S. pombe homolog of vertebrate pRab46/48, which is involved in histone H3 incorporation into chromatin. In vertebrates, the two isoforms Mis18α/β form a complex with M18BP1, also known as KNL-2. Depletion of pRab46/48 or Mis18α/β in human cells reduces CENP-A incorporation into centromeres, suggesting a conserved role for these proteins.

The timing of CENP-A incorporation is regulated by Mis18α/β, which is recruited to centromeres at least in part via Mis18BP1 binding to CENP-C. Mis18α/β starts to localize to centromeres during anaphase and remains there during telophase. Its levels fall dramatically in G1 phase. Mis18α/β thus appears to function as a licensing factor for CENP-A incorporation (Figure 6).

The Mis18 complex must be phosphorylated by Polo-like kinase 1 (Plk1) during G1 to facilitate CENP-A incorporation. Because CDK1 activity negatively regulates Mis18 complex-derived CENP-A incorporation, CENP-A incorporation might be controlled by a two-step regulatory mechanism governed by Plk1 and CDK1.

The Mis18 complex does not directly bind to soluble CENP-A. Instead a CENP-A-specific chaperone, HJURP, binds soluble CENP-A-H4 complex before its chromatin incorporation during G1 phase (Figure 6). The yeast and Drosophila homologs of HJURP are apparently Scm3 and Cal1, respectively. Scm3 is found in hexameric Cse4 nucleosomes, which appear to be assembly intermediates. The mechanism of CENP-A incorporation is thus widely conserved. Current data suggest that the Mis18 complex licenses centromeric chromatin by binding and recruiting a complex of HJURP-CENP-A-H4 (Figure 6).

The timing of CENP-A incorporation is critical for kinetochore assembly and function. If CENP-A incorporation is artificially deregulated by constitutive targeting of Mis18α to centromeres (this causes constitutive insertion of CENP-A across the cell cycle), then mitotic kinetochore function is strongly disrupted. It is not known why unscheduled incorporation of CENP-A has such a strong disruptive effect.

How Does CENP-A Chromatin Become Competent for Kinetochore Assembly?

With the exception of Trypanosomids, CENP-A containing chromatin is a near universal feature of centromere specification. Yet with few examples, targeting of ectopic CENP-A is not sufficient to trigger centromere formation. Indeed, because most chromosomal CENP-A is incorporated at ectopic sites that lack centromere activity, this begs the question of how cells distinguish centromeric CENP-A from ectopic CENP-A. It is possible that additional modifications might “license” CENP-A containing chromatin, making it competent for kinetochore assembly. A recent study revealed that histone H4 Lys20 monomethylation (H4K20me1) specifically occurs at centromeric CENP-A chromatin. Because reducing H4K20me1 levels at centromeres causes mislocalization of CENP-H and CENP-T, this modification might help render CENP-A chromatin competent for kinetochore assembly (Figure 6). Other histone modifications of CENP-A nucleosomes or of centromeric nucleosomes containing canonical H3 might also be involved in formation of functional centromeric chromatin, possibly by influencing interactions with other kinetochore proteins such as CENP-C or CENP-N, which bind to CENP-A nucleosomes concentrated in centromeres.

Understanding the mechanisms by which CENP-A chromatin induces subsequent kinetochore assembly remains an important area for future studies.

Centromeric Chromatin Contributes to Sister Chromatid Cohesion

In addition to serving as a mark for kinetochore assembly, centromeric chromatin also contributes to chromosome segregation by binding cohesin and the chromosomal passenger complex (CPC) of Aurora B kinase, INCENP, Survivin, and Borealin.

Cohesin regulates the cohesion of sister chromatids so that kinetochores can orient to opposite spindle poles and chromosomes can segregate equally during mitosis. Pericentromeric heterochromatin in S. pombe recruits cohesin, and the link between heterochromatin and cohesin is conserved in other organisms. Cohesin is also concentrated in the pericentromere in budding yeast where there is no canonical heterochromatin. Cohesion at centromeres is protected by proteins of the shugoshin family, which have recently been observed to also function in recruitment of the CPC.

Shugoshin (Sgo1) forms part of a two-part mechanism for recruiting the CPC to centromeric heterochromatin. First, the checkpoint kinase Bub1 phosphorylates histone H2A at threonine 120 (H2AT120ph) in inner centromeres. Sgo1 binds to this histone mark and then recruits the CPC via an interaction with Borealin. Second, Haspin kinase phosphorylation of histone H3 threonine 3 (H3T3ph). Survivin binding to this histone mark is required for CPC targeting to centromeres. At centromeres, the CPC regulates kinetochore-microtubule interactions by phosphorylation of several kinetochore proteins and regulates spindle checkpoint signaling to delay mitotic progression if there are incorrect kinetochore-microtubule attachments.

Histone-fold Proteins that Bridge between the Centromere and Kinetochore

CENP-A and H3 nucleosomes are not the only proteins that directly bind to centromeric DNA and contribute to the formation of centromere-specific chromatin. Experiments aimed at isolating unknown centromere proteins identified CENP-T, CENP-W, CENP-S, and CENP-X, all of which directly bind to centromeric DNA. These proteins have histone folds and make a tetrameric CENP-T-W-S-X complex. Because this complex can induce supercoils into DNA and its DNA binding surface resembles that of canonical nucleosomes, it might form a nucleosome-like structure at centromeres.

Interestingly, the CENP-T-W-S-X complex induces positive supercoils into DNA, whereas canonical histones induce negative supercoils. Analysis of yeast mini-chromosomes suggested that there are positive supercoils in centromere chromatin. Thus, in addition to CENP-A nucleosomes, the CENP-T-W-S-X nucleosome-like complex might contribute to formation of centromere-specific chromatin (Figure 7).

Although CENP-T-W-S-X tetramers are critical for centromere function, chromosome segregation still occurs in CENP-S- or CENP-X-deficient cells. This suggests that CENP-T-W and CENP-S-X can function independently. Indeed, CENP-S-X binds FANCM proteins at DNA damage sites. Further studies are needed to clarify how CENP-T-W, CENP-S-X, and CENP-T-W-S-X bind to DNA and how the tetramer contributes to formation of centromeric chromatin.

Artificial Kinetochores Bypass the Need for Centromere-Specific Chromatin

One key function of the centromere is to regulate chromosomal interactions with microtubules. This interaction requires the Ndc80 complex in the kinetochore. This suggested that if the Ndc80 complex could be artificially localized to an ectopic chromosomal locus, then that locus might function as an artificial kinetochore and direct chromosome segregation.

The CENP-T N-terminal region directly binds to the Ndc80 complex, while its C terminus contacts the centromeric DNA. Remarkably, tethering the CENP-T N terminus at a noncentromeric locus using the LacI-LacO system resulted in creation of an artificial kinetochore that efficiently directed chromosome segregation following deletion of the natural centromere of the corresponding chromosome in chicken DT40 cells. A second artificial kinetochore was also constructed by similar tethering of CENP-C to a Lac operator array. CENP-C recruits the Mis12 complex, which binds the Ndc80 complex (,,; Figure 7). Surprisingly, many centromere proteins, including CENP-A, were not detected in either artificial kinetochore. Together, these experiments reveal that recruiting the Ndc80 complex to centromeres is a major function of centromere chromatin. Thus, artificial recruitment of the complex can bypass the need for centromere-specific chromatin structure during kinetochore formation.

CENP-A-mediated artificial kinetochores also have been created in human, chicken, and Drosophila cells (Figure 7). In another approach, several aspects of kinetochore function were reconstituted in vitro on CENP-A nucleosome-coated beads using Xenopus egg extracts.

Artificial kinetochores are promising tools for kinetochore studies and genetic engineering. It will therefore be important to determine the efficiency with which they are able to direct chromosome segregation in animals and their ability to cope with attachment errors, which are a natural hazard of mitotic chromosome segregation.

Perspectives

Even though centromeric chromatin can form both on specialized (often repetitive) DNA sequences and on other sequences that are not normally centromeric, its structure and composition are distinct from that of other chromatin regions. Centromeric chromatin consists of a relatively small number of CENP-A-containing nucleosomes distributed among centromere-specific H3 nucleosomes together with additional specialized DNA-binding proteins including the CENP-T-W-S-X complex (Figure 7). The centromere-specific chromatin structure is established by coordination of these factors with modification of the CENP-A nucleosomes, and together this lays the essential foundation for functional kinetochore assembly. Throughout this review, we have stressed that kinetochore function is distinct from centromeric chromatin. However, because kinetochores assemble on the surface of centromeres, it can be difficult to separate the functions of the two. By bypassing centromere function, artificial kinetochores might provide an excellent tool to tackle this issue.

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    Baum M., Ngan V.K., Clarke L. The centromeric K-type repeat and the central core are together sufficient to establish a functional Schizosaccharomyces pombe centromere. Mol. Biol. Cell. 1994;5:747-761.

    Not in our library10.1091/mbc.5.7.747

  7. 7.

    Baum M., Sanyal K., Mishra P.K., Thaler N., Carbon J. Formation of functional centromeric chromatin is specified epigenetically in Candida albicans. Proc. Natl. Acad. Sci. USA. 2006;103:14877-14882.

    Not in our library10.1073/pnas.0606958103

  8. 8.

    Beadle G.W. A Possible Influence of the Spindle Fibre on Crossing-Over in Drosophila. Proc. Natl. Acad. Sci. USA. 1932;18:160-165.

    Not in our library10.1073/pnas.18.2.160

  9. 9.

    Bergmann J.H., Rodríguez M.G., Martins N.M., Kimura H., Kelly D.A., Masumoto H., Larionov V., Jansen L.E., Earnshaw W.C. Epigenetic engineering shows H3K4me2 is required for HJURP targeting and CENP-A assembly on a synthetic human kinetochore. EMBO J. 2011;30:328-340.

    Not in our library10.1038/emboj.2010.329

  10. 10.

    Bergmann J.H., Jakubsche J.N., Martins N.M., Kagansky A., Nakano M., Kimura H., Kelly D.A., Turner B.M., Masumoto H., Larionov V., Earnshaw W.C. Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function. J. Cell Sci. 2012;125:411-421.

    Not in our library10.1242/jcs.090639

  11. 11.

    Black B.E., Cleveland D.W. Epigenetic centromere propagation and the nature of CENP-a nucleosomes. Cell. 2011;144:471-479.

    Not in our library10.1016/j.cell.2011.02.002

  12. 12.

    Black B.E., Foltz D.R., Chakravarthy S., Luger K., Woods V.L., Cleveland D.W. Structural determinants for generating centromeric chromatin. Nature. 2004;430:578-582.

    Not in our library10.1038/nature02766

  13. 13.

    Black B.E., Brock M.A., Bédard S., Woods V.L., Cleveland D.W. An epigenetic mark generated by the incorporation of CENP-A into centromeric nucleosomes. Proc. Natl. Acad. Sci. USA. 2007;104:5008-5013.

    Not in our library10.1073/pnas.0700390104

  14. 14.

    Bloom K.S., Carbon J. Yeast centromere DNA is in a unique and highly ordered structure in chromosomes and small circular minichromosomes. Cell. 1982;29:305-317.

    Not in our library10.1016/0092-8674(82)90147-7

  15. 15.

    Blower M.D., Sullivan B.A., Karpen G.H. Conserved organization of centromeric chromatin in flies and humans. Dev. Cell. 2002;2:319-330.

    Not in our library10.1016/s1534-5807(02)00135-1

  16. 16.
    The quantitative architecture of centromeric chromatin · 2014
    No notice
  17. 17.

    Brinkley B.R., Stubblefield E. The fine structure of the kinetochore of a mammalian cell in vitro. Chromosoma. 1966;19:28-43.

    Not in our library10.1007/bf00332792

  18. 18.

    Bui M., Dimitriadis E.K., Hoischen C., An E., Quénet D., Giebe S., Nita-Lazar A., Diekmann S., Dalal Y. Cell-cycle-dependent structural transitions in the human CENP-A nucleosome in vivo. Cell. 2012;150:317-326.

    Not in our library10.1016/j.cell.2012.05.035

  19. 19.

    Camahort R., Li B., Florens L., Swanson S.K., Washburn M.P., Gerton J.L. Scm3 is essential to recruit the histone h3 variant cse4 to centromeres and to maintain a functional kinetochore. Mol. Cell. 2007;26:853-865.

    Not in our library10.1016/j.molcel.2007.05.013

  20. 20.

    Camahort R., Shivaraju M., Mattingly M., Li B., Nakanishi S., Zhu D., Shilatifard A., Workman J.L., Gerton J.L. Cse4 is part of an octameric nucleosome in budding yeast. Mol. Cell. 2009;35:794-805.

    Not in our library10.1016/j.molcel.2009.07.022

  21. 21.

    Cardinale S., Bergmann J.H., Kelly D., Nakano M., Valdivia M.M., Kimura H., Masumoto H., Larionov V., Earnshaw W.C. Hierarchical inactivation of a synthetic human kinetochore by a chromatin modifier. Mol. Biol. Cell. 2009;20:4194-4204.

    Not in our library10.1091/mbc.e09-06-0489

  22. 22.

    Carmena M., Wheelock M., Funabiki H., Earnshaw W.C. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat. Rev. Mol. Cell Biol. 2012;13:789-803.

    Not in our library10.1038/nrm3474

  23. 23.

    Carroll C.W., Silva M.C., Godek K.M., Jansen L.E., Straight A.F. Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N. Nat. Cell Biol. 2009;11:896-902.

    Not in our library10.1038/ncb1899

  24. 24.

    Centola M., Carbon J. Cloning and characterization of centromeric DNA from Neurospora crassa. Mol. Cell. Biol. 1994;14:1510-1519.

    Not in our library10.1128/mcb.14.2.1510-1519.1994

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    Chan F.L., Marshall O.J., Saffery R., Kim B.W., Earle E., Choo K.H., Wong L.H. Active transcription and essential role of RNA polymerase II at the centromere during mitosis. Proc. Natl. Acad. Sci. USA. 2012;109:1979-1984.

    Not in our library10.1073/pnas.1108705109

  26. 26.

    Cheeseman I.M., Desai A. Molecular architecture of the kinetochore-microtubule interface. Nat. Rev. Mol. Cell Biol. 2008;9:33-46.

    Not in our library10.1038/nrm2310

  27. 27.

    Cheeseman I.M., Chappie J.S., Wilson-Kubalek E.M., Desai A. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell. 2006;127:983-997.

    Not in our library10.1016/j.cell.2006.09.039

  28. 28.

    Chen E.S., Zhang K., Nicolas E., Cam H.P., Zofall M., Grewal S.I. Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature. 2008;451:734-737.

    Not in our library10.1038/nature06561

  29. 29.

    Clarke L. Centromeres: proteins, protein complexes, and repeated domains at centromeres of simple eukaryotes. Curr. Opin. Genet. Dev. 1998;8:212-218.

    Not in our library10.1016/s0959-437x(98)80143-3

  30. 30.

    Coffman V.C., Wu P., Parthun M.R., Wu J.Q. CENP-A exceeds microtubule attachment sites in centromere clusters of both budding and fission yeast. J. Cell Biol. 2011;195:563-572.

    Not in our library10.1083/jcb.201106078

  31. 31.

    Cooke C.A., Bazett-Jones D.P., Earnshaw W.C., Rattner J.B. Mapping DNA within the mammalian kinetochore. J. Cell Biol. 1993;120:1083-1091.

    Not in our library10.1083/jcb.120.5.1083

  32. 32.

    Copenhaver G.P., Nickel K., Kuromori T., Benito M.I., Kaul S., Lin X., Bevan M., Murphy G., Harris B., Parnell L.D. Genetic definition and sequence analysis of Arabidopsis centromeres. Science. 1999;286:2468-2474.

    Not in our library10.1126/science.286.5449.2468

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    Dalal Y., Furuyama T., Vermaak D., Henikoff S. Structure, dynamics, and evolution of centromeric nucleosomes. Proc. Natl. Acad. Sci. USA. 2007;104:15974-15981.

    Not in our library10.1073/pnas.0707648104

  34. 34.

    Dambacher S., Deng W., Hahn M., Sadic D., Fröhlich J., Nuber A., Hoischen C., Diekmann S., Leonhardt H., Schotta G. CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin. Nucleus. 2012;3:101-110.

    Not in our library10.4161/nucl.18955

  35. 35.

    Darlington C.D. The external mechanics of chromosomes. Proc. R. Soc. Lond. B Biol. Sci. 1936;121:264-319.

    Not in our library

  36. 36.

    DeLuca J.G., Gall W.E., Ciferri C., Cimini D., Musacchio A., Salmon E.D. Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. Cell. 2006;127:969-982.

    Not in our library10.1016/j.cell.2006.09.047

  37. 37.

    Dimitriadis E.K., Weber C., Gill R.K., Diekmann S., Dalal Y. Tetrameric organization of vertebrate centromeric nucleosomes. Proc. Natl. Acad. Sci. USA. 2010;107:20317-20322.

    Not in our library10.1073/pnas.1009563107

  38. 38.

    Dunleavy E.M., Roche D., Tagami H., Lacoste N., Ray-Gallet D., Nakamura Y., Daigo Y., Nakatani Y., Almouzni-Pettinotti G. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell. 2009;137:485-497.

    Not in our library10.1016/j.cell.2009.02.040

  39. 39.

    Dunleavy E.M., Almouzni G., Karpen G.H. H3.3 is deposited at centromeres in S phase as a placeholder for newly assembled CENP-A in G1 phase. Nucleus. 2011;2:146-157.

    Not in our library10.4161/nucl.2.2.15211

  40. 40.

    Earnshaw W.C., Migeon B.R. Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome. Chromosoma. 1985;92:290-296.

    Not in our library10.1007/bf00329812

  41. 41.

    Earnshaw W.C., Rothfield N. Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma. Chromosoma. 1985;91:313-321.

    Not in our library10.1007/bf00328227

  42. 42.

    Earnshaw W.C., Sullivan K.F., Machlin P.S., Cooke C.A., Kaiser D.A., Pollard T.D., Rothfield N.F., Cleveland D.W. Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen. J. Cell Biol. 1987;104:817-829.

    Not in our library10.1083/jcb.104.4.817

  43. 43.

    Earnshaw W.C., Ratrie H., Stetten G. Visualization of centromere proteins CENP-B and CENP-C on a stable dicentric chromosome in cytological spreads. Chromosoma. 1989;98:1-12.

    Not in our library10.1007/bf00293329

  44. 44.

    Earnshaw W.C., Allshire R.C., Black B.E., Bloom K., Brinkley B.R., Brown W., Cheeseman I.M., Choo K.H., Copenhaver G.P., Deluca J.G. Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant. Chromosome Res. 2013;21:101-106.

    Not in our library10.1007/s10577-013-9347-y

  45. 45.

    Ebersole T.A., Ross A., Clark E., McGill N., Schindelhauer D., Cooke H., Grimes B. Mammalian artificial chromosome formation from circular alphoid input DNA does not require telomere repeats. Hum. Mol. Genet. 2000;9:1623-1631.

    Not in our library10.1093/hmg/9.11.1623

  46. 46.

    Ekwall K. Epigenetic control of centromere behavior. Annu. Rev. Genet. 2007;41:63-81.

    Not in our library10.1146/annurev.genet.41.110306.130127

  47. 47.

    Erhardt S., Mellone B.G., Betts C.M., Zhang W., Karpen G.H., Straight A.F. Genome-wide analysis reveals a cell cycle-dependent mechanism controlling centromere propagation. J. Cell Biol. 2008;183:805-818.

    Not in our library10.1083/jcb.200806038

  48. 48.

    Folco H.D., Pidoux A.L., Urano T., Allshire R.C. Heterochromatin and RNAi are required to establish CENP-A chromatin at centromeres. Science. 2008;319:94-97.

    Not in our library10.1126/science.1150944

  49. 49.

    Foltz D.R., Jansen L.E., Black B.E., Bailey A.O., Yates J.R., Cleveland D.W. The human CENP-A centromeric nucleosome-associated complex. Nat. Cell Biol. 2006;8:458-469.

    Not in our library10.1038/ncb1397

  50. 50.

    Foltz D.R., Jansen L.E., Bailey A.O., Yates J.R., Bassett E.A., Wood S., Black B.E., Cleveland D.W. Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP. Cell. 2009;137:472-484.

    Not in our library10.1016/j.cell.2009.02.039

  51. 51.

    Fujita Y., Hayashi T., Kiyomitsu T., Toyoda Y., Kokubu A., Obuse C., Yanagida M. Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Dev. Cell. 2007;12:17-30.

    Not in our library10.1016/j.devcel.2006.11.002

  52. 52.

    Furuyama S., Biggins S. Centromere identity is specified by a single centromeric nucleosome in budding yeast. Proc. Natl. Acad. Sci. USA. 2007;104:14706-14711.

    Not in our library10.1073/pnas.0706985104

  53. 53.

    Furuyama T., Henikoff S. Centromeric nucleosomes induce positive DNA supercoils. Cell. 2009;138:104-113.

    Not in our library10.1016/j.cell.2009.04.049

  54. 54.

    Gartenberg M. Heterochromatin and the cohesion of sister chromatids. Chromosome Res. 2009;17:229-238.

    Not in our library10.1007/s10577-008-9012-z

  55. 55.

    Gascoigne K.E., Takeuchi K., Suzuki A., Hori T., Fukagawa T., Cheeseman I.M. Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes. Cell. 2011;145:410-422.

    Not in our library10.1016/j.cell.2011.03.031

  56. 56.

    Gassmann R., Rechtsteiner A., Yuen K.W., Muroyama A., Egelhofer T., Gaydos L., Barron F., Maddox P., Essex A., Monen J. An inverse relationship to germline transcription defines centromeric chromatin in C. elegans. Nature. 2012;484:534-537.

    Not in our library10.1038/nature10973

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    Guse A., Carroll C.W., Moree B., Fuller C.J., Straight A.F. In vitro centromere and kinetochore assembly on defined chromatin templates. Nature. 2011;477:354-358.

    Not in our library10.1038/nature10379

  58. 58.

    Gutiérrez-Caballero C., Cebollero L.R., Pendás A.M. Shugoshins: from protectors of cohesion to versatile adaptors at the centromere. Trends Genet. 2012;28:351-360.

    Not in our library10.1016/j.tig.2012.03.003

  59. 59.

    Harrington J.J., Van Bokkelen G., Mays R.W., Gustashaw K., Willard H.F. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nat. Genet. 1997;15:345-355.

    Not in our library10.1038/ng0497-345

  60. 60.

    Hasson D., Panchenko T., Salimian K.J., Salman M.U., Sekulic N., Alonso A., Warburton P.E., Black B.E. The octamer is the major form of CENP-A nucleosomes at human centromeres. Nat. Struct. Mol. Biol. 2013;20:687-695.

    Not in our library10.1038/nsmb.2562

  61. 61.

    Hayashi T., Fujita Y., Iwasaki O., Adachi Y., Takahashi K., Yanagida M. Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres. Cell. 2004;118:715-729.

    Not in our library10.1016/j.cell.2004.09.002

  62. 62.

    Hegemann J.H., Fleig U.N. The centromere of budding yeast. Bioessays. 1993;15:451-460.

    Not in our library10.1002/bies.950150704

  63. 63.

    Hori T., Amano M., Suzuki A., Backer C.B., Welburn J.P., Dong Y., McEwen B.F., Shang W.H., Suzuki E., Okawa K. CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell. 2008;135:1039-1052.

    Not in our library10.1016/j.cell.2008.10.019

  64. 64.

    Hori T., Shang W.H., Takeuchi K., Fukagawa T. The CCAN recruits CENP-A to the centromere and forms the structural core for kinetochore assembly. J. Cell Biol. 2013;200:45-60.

    Not in our library10.1083/jcb.201210106

  65. 65.

    Hori T., Shang W.H., Toyoda A., Misu S., Monma N., Ikeo K., Molina O., Vargiu G., Fujiyama A., Kimura H. Histone H4 Lys 20 monomethylation of the CENP-A nucleosome is essential for kinetochore assembly. Dev. Cell. 2014;29:740-749.

    Not in our library10.1016/j.devcel.2014.05.001

  66. 66.

    Hudson D.F., Fowler K.J., Earle E., Saffery R., Kalitsis P., Trowell H., Hill J., Wreford N.G., de Kretser D.M., Cancilla M.R. Centromere protein B null mice are mitotically and meiotically normal but have lower body and testis weights. J. Cell Biol. 1998;141:309-319.

    Not in our library10.1083/jcb.141.2.309

  67. 67.

    Hughes-Schrader S., Ris H. The diffuse spindle attachment of coccids, verified by the mitotic behavior of induced chromosome fragments. J. Exp. Zool. 1941;87:429-456.

    Not in our library

  68. 68.

    Ikeno M., Grimes B., Okazaki T., Nakano M., Saitoh K., Hoshino H., McGill N.I., Cooke H., Masumoto H. Construction of YAC-based mammalian artificial chromosomes. Nat. Biotechnol. 1998;16:431-439.

    Not in our library10.1038/nbt0598-431

  69. 69.

    Ishii K., Ogiyama Y., Chikashige Y., Soejima S., Masuda F., Kakuma T., Hiraoka Y., Takahashi K. Heterochromatin integrity affects chromosome reorganization after centromere dysfunction. Science. 2008;321:1088-1091.

    Not in our library10.1126/science.1158699

  70. 70.

    Jansen L.E., Black B.E., Foltz D.R., Cleveland D.W. Propagation of centromeric chromatin requires exit from mitosis. J. Cell Biol. 2007;176:795-805.

    Not in our library10.1083/jcb.200701066

  71. 71.

    Joglekar A.P., Bouck D., Finley K., Liu X., Wan Y., Berman J., He X., Salmon E.D., Bloom K.S. Molecular architecture of the kinetochore-microtubule attachment site is conserved between point and regional centromeres. J. Cell Biol. 2008;181:587-594.

    Not in our library10.1083/jcb.200803027

  72. 72.

    Joglekar A.P., Bloom K., Salmon E.D. In vivo protein architecture of the eukaryotic kinetochore with nanometer scale accuracy. Curr. Biol. 2009;19:694-699.

    Not in our library10.1016/j.cub.2009.02.056

  73. 73.

    Johnston K., Joglekar A., Hori T., Suzuki A., Fukagawa T., Salmon E.D. Vertebrate kinetochore protein architecture: protein copy number. J. Cell Biol. 2010;189:937-943.

    Not in our library10.1083/jcb.200912022

  74. 74.

    Jokelainen P.T. The ultrastructure and spatial organization of the metaphase kinetochore in mitotic rat cells. J. Ultrastruct. Res. 1967;19:19-44.

    Not in our library10.1016/s0022-5320(67)80058-3

  75. 75.

    Kapoor M., Montes de Oca Luna R., Liu G., Lozano G., Cummings C., Mancini M., Ouspenski I., Brinkley B.R., May G.S. The cenpB gene is not essential in mice. Chromosoma. 1998;107:570-576.

    Not in our library10.1007/s004120050343

  76. 76.

    Kato H., Jiang J., Zhou B.R., Rozendaal M., Feng H., Ghirlando R., Xiao T.S., Straight A.F., Bai Y. A conserved mechanism for centromeric nucleosome recognition by centromere protein CENP-C. Science. 2013;340:1110-1113.

    Not in our library10.1126/science.1235532

  77. 77.

    Kawashima S.A., Tsukahara T., Langegger M., Hauf S., Kitajima T.S., Watanabe Y. Shugoshin enables tension-generating attachment of kinetochores by loading Aurora to centromeres. Genes Dev. 2007;21:420-435.

    Not in our library10.1101/gad.1497307

  78. 78.

    Kelly A.E., Ghenoiu C., Xue J.Z., Zierhut C., Kimura H., Funabiki H. Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science. 2010;330:235-239.

    Not in our library10.1126/science.1189505

  79. 79.
    Neocentromeres Form Efficiently at Multiple Possible Loci in Candida albicans · 2009
    No notice
  80. 80.

    Kiburz B.M., Reynolds D.B., Megee P.C., Marston A.L., Lee B.H., Lee T.I., Levine S.S., Young R.A., Amon A. The core centromere and Sgo1 establish a 50-kb cohesin-protected domain around centromeres during meiosis I. Genes Dev. 2005;19:3017-3030.

    Not in our library10.1101/gad.1373005

  81. 81.

    Kitagawa T., Ishii K., Takeda K., Matsumoto T. The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin. Nature Communications. 2014;5:3597.

    Not in our library10.1038/ncomms4597

  82. 82.

    Kouprina N., Earnshaw W.C., Masumoto H., Larionov V. A new generation of human artificial chromosomes for functional genomics and gene therapy. Cell. Mol. Life Sci. 2013;70:1135-1148.

    Not in our library10.1007/s00018-012-1113-3

  83. 83.

    Lacoste N., Woolfe A., Tachiwana H., Garea A.V., Barth T., Cantaloube S., Kurumizaka H., Imhof A., Almouzni G. Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX. Mol. Cell. 2014;53:631-644.

    Not in our library10.1016/j.molcel.2014.01.018

  84. 84.
    Quantitative single-molecule microscopy reveals that CENP-A Cnp1 deposition occurs during G2 in fission yeast · 2012
    No notice
  85. 85.

    Lawrimore J., Bloom K.S., Salmon E.D. Point centromeres contain more than a single centromere-specific Cse4 (CENP-A) nucleosome. J. Cell Biol. 2011;195:573-582.

    Not in our library10.1083/jcb.201106036

  86. 86.
    Efficient yeast ChIP-Seq using multiplex short-read DNA sequencing · 2009
    No notice
  87. 87.
    Centromere-like regions in the budding yeast genome. · 2013
    Not checked
  88. 88.

    Locke D.P., Hillier L.W., Warren W.C., Worley K.C., Nazareth L.V., Muzny D.M., Yang S.P., Wang Z., Chinwalla A.T., Minx P. Comparative and demographic analysis of orang-utan genomes. Nature. 2011;469:529-533.

    Not in our library10.1038/nature09687

  89. 89.

    Luykx P. The structure of the kinetochore in meiosis and mitosis in Urechis eggs. Exp. Cell Res. 1965;39:643-657.

    Not in our library10.1016/0014-4827(65)90068-6

  90. 90.

    Maddox P.S., Hyndman F., Monen J., Oegema K., Desai A. Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. J. Cell Biol. 2007;176:757-763.

    Not in our library10.1083/jcb.200701065

  91. 91.

    Maiato H., DeLuca J., Salmon E.D., Earnshaw W.C. The dynamic kinetochore-microtubule interface. J. Cell Sci. 2004;117:5461-5477.

    Not in our library10.1242/jcs.01536

  92. 92.

    Manuelidis L. Chromosomal localization of complex and simple repeated human DNAs. Chromosoma. 1978;66:23-32.

    Not in our library10.1007/bf00285813

  93. 93.

    Marshall O.J., Chueh A.C., Wong L.H., Choo K.H. Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution. Am. J. Hum. Genet. 2008;82:261-282.

    Not in our library10.1016/j.ajhg.2007.11.009

  94. 94.

    McKay R.D. The mechanism of G and C banding in mammalian metaphase chromosomes. Chromosoma. 1973;44:1-14.

    Not in our library10.1007/bf00372569

  95. 95.

    McKinley K.L., Cheeseman I.M. Polo-like Kinase 1 Licenses CENP-A Deposition at Centromeres. Cell. 2014;158:397-411.

    Not in our library10.1016/j.cell.2014.06.016

  96. 96.

    Mendiburo M.J., Padeken J., Fülöp S., Schepers A., Heun P. Drosophila CENH3 is sufficient for centromere formation. Science. 2011;334:686-690.

    Not in our library10.1126/science.1206880

  97. 97.

    Miell M.D., Fuller C.J., Guse A., Barysz H.M., Downes A., Owen-Hughes T., Rappsilber J., Straight A.F., Allshire R.C. CENP-A confers a reduction in height on octameric nucleosomes. Nat. Struct. Mol. Biol. 2013;20:763-765.

    Not in our library10.1038/nsmb.2574

  98. 98.

    Miga K.H., Newton Y., Jain M., Altemose N., Willard H.F., Kent W.J. Centromere reference models for human chromosomes X and Y satellite arrays. Genome Res. 2014;24:697-707.

    Not in our library10.1101/gr.159624.113

  99. 99.

    Minc E., Allory Y., Worman H.J., Courvalin J.C., Buendia B. Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells. Chromosoma. 1999;108:220-234.

    Not in our library10.1007/s004120050372

  100. 100.

    Mizuguchi G., Xiao H., Wisniewski J., Smith M.M., Wu C. Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes. Cell. 2007;129:1153-1164.

    Not in our library10.1016/j.cell.2007.04.026

  101. 101.

    Moree B., Meyer C.B., Fuller C.J., Straight A.F. CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly. J. Cell Biol. 2011;194:855-871.

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    Moroi Y., Peebles C., Fritzler M.J., Steigerwald J., Tan E.M. Autoantibody to centromere (kinetochore) in scleroderma sera. Proc. Natl. Acad. Sci. USA. 1980;77:1627-1631.

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    Murphy T.D., Karpen G.H. Localization of centromere function in a Drosophila minichromosome. Cell. 1995;82:599-609.

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    Murray A.W., Szostak J.W. Construction of artificial chromosomes in yeast. Nature. 1983;305:189-193.

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    Nagaki K., Cheng Z., Ouyang S., Talbert P.B., Kim M., Jones K.M., Henikoff S., Buell C.R., Jiang J. Sequencing of a rice centromere uncovers active genes. Nat. Genet. 2004;36:138-145.

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    Inactivation of a Human Kinetochore by Specific Targeting of Chromatin Modifiers · 2008
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    Nakashima H., Nakano M., Ohnishi R., Hiraoka Y., Kaneda Y., Sugino A., Masumoto H. Assembly of additional heterochromatin distinct from centromere-kinetochore chromatin is required for de novo formation of human artificial chromosome. J. Cell Sci. 2005;118:5885-5898.

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    Nasmyth K., Haering C.H. Cohesin: its roles and mechanisms. Annu. Rev. Genet. 2009;43:525-558.

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    Nasuda S., Hudakova S., Schubert I., Houben A., Endo T.R. Stable barley chromosomes without centromeric repeats. Proc. Natl. Acad. Sci. USA. 2005;102:9842-9847.

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    Nishino T., Takeuchi K., Gascoigne K.E., Suzuki A., Hori T., Oyama T., Morikawa K., Cheeseman I.M., Fukagawa T. CENP-T-W-S-X forms a unique centromeric chromatin structure with a histone-like fold. Cell. 2012;148:487-501.

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    Nishino T., Rago F., Hori T., Tomii K., Cheeseman I.M., Fukagawa T. CENP-T provides a structural platform for outer kinetochore assembly. EMBO J. 2013;32:424-436.

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    Nonaka N., Kitajima T., Yokobayashi S., Xiao G., Yamamoto M., Grewal S.I., Watanabe Y. Recruitment of cohesin to heterochromatic regions by Swi6/HP1 in fission yeast. Nat. Cell Biol. 2002;4:89-93.

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    Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A. DNA sequence and analysis of human chromosome 8. Nature. 2006;439:331-335.

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    Ohzeki J., Nakano M., Okada T., Masumoto H. CENP-B box is required for de novo centromere chromatin assembly on human alphoid DNA. J. Cell Biol. 2002;159:765-775.

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    Ohzeki J., Bergmann J.H., Kouprina N., Noskov V.N., Nakano M., Kimura H., Earnshaw W.C., Larionov V., Masumoto H. Breaking the HAC Barrier: histone H3K9 acetyl/methyl balance regulates CENP-A assembly. EMBO J. 2012;31:2391-2402.

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    Okada M., Cheeseman I.M., Hori T., Okawa K., McLeod I.X., Yates J.R., Desai A., Fukagawa T. The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nat. Cell Biol. 2006;8:446-457.

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    Okada T., Ohzeki J., Nakano M., Yoda K., Brinkley W.R., Larionov V., Masumoto H. CENP-B controls centromere formation depending on the chromatin context. Cell. 2007;131:1287-1300.

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    Palmer D.K., O’Day K., Wener M.H., Andrews B.S., Margolis R.L. A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J. Cell Biol. 1987;104:805-815.

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    Pardue M.L., Gall J.G. Chromosomal localization of mouse satellite DNA. Science. 1970;168:1356-1358.

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    Perez-Castro A.V., Shamanski F.L., Meneses J.J., Lovato T.L., Vogel K.G., Moyzis R.K., Pedersen R. Centromeric protein B null mice are viable with no apparent abnormalities. Dev. Biol. 1998;201:135-143.

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    Pluta A.F., Mackay A.M., Ainsztein A.M., Goldberg I.G., Earnshaw W.C. The centromere: hub of chromosomal activities. Science. 1995;270:1591-1594.

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    Ranjitkar P., Press M.O., Yi X., Baker R., MacCoss M.J., Biggins S. An E3 ubiquitin ligase prevents ectopic localization of the centromeric histone H3 variant via the centromere targeting domain. Mol. Cell. 2010;40:455-464.

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    Ribeiro S.A., Vagnarelli P., Dong Y., Hori T., McEwen B.F., Fukagawa T., Flors C., Earnshaw W.C. A super-resolution map of the vertebrate kinetochore. Proc. Natl. Acad. Sci. USA. 2010;107:10484-10489.

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    Sanyal K., Baum M., Carbon J. Centromeric DNA sequences in the pathogenic yeast Candida albicans are all different and unique. Proc. Natl. Acad. Sci. USA. 2004;101:11374-11379.

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    Schrader F. Kinetic Regions in Chromosomes. Nature. 1939;143:122.

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    Screpanti E., De Antoni A., Alushin G.M., Petrovic A., Melis T., Nogales E., Musacchio A. Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. Curr. Biol. 2011;21:391-398.

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    Sekulic N., Bassett E.A., Rogers D.J., Black B.E. The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres. Nature. 2010;467:347-351.

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    Shang W.H., Hori T., Toyoda A., Kato J., Popendorf K., Sakakibara Y., Fujiyama A., Fukagawa T. Chickens possess centromeres with both extended tandem repeats and short non-tandem-repetitive sequences. Genome Res. 2010;20:1219-1228.

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    Chromosome Engineering Allows the Efficient Isolation of Vertebrate Neocentromeres · 2013
    No notice
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    Shelby R.D., Vafa O., Sullivan K.F. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites. J. Cell Biol. 1997;136:501-513.

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    Shivaraju M., Unruh J.R., Slaughter B.D., Mattingly M., Berman J., Gerton J.L. Cell-cycle-coupled structural oscillation of centromeric nucleosomes in yeast. Cell. 2012;150:304-316.

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    Silva M.C., Bodor D.L., Stellfox M.E., Martins N.M., Hochegger H., Foltz D.R., Jansen L.E. Cdk activity couples epigenetic centromere inheritance to cell cycle progression. Dev. Cell. 2012;22:52-63.

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    Singh T.R., Saro D., Ali A.M., Zheng X.F., Du C.H., Killen M.W., Sachpatzidis A., Wahengbam K., Pierce A.J., Xiong Y. MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol. Cell. 2010;37:879-886.

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  145. 145.

    Steiner F.A., Henikoff S. Holocentromeres are dispersed point centromeres localized at transcription factor hotspots. eLife. 2014;3:e02025.

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    Stoler S., Keith K.C., Curnick K.E., Fitzgerald-Hayes M. A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis. Genes Dev. 1995;9:573-586.

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  147. 147.

    Sullivan B.A., Karpen G.H. Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat. Struct. Mol. Biol. 2004;11:1076-1083.

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    Sullivan L.L., Boivin C.D., Mravinac B., Song I.Y., Sullivan B.A. Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells. Chromosome Res. 2011;19:457-470.

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  149. 149.

    Sun X., Le H.D., Wahlstrom J.M., Karpen G.H. Sequence analysis of a functional Drosophila centromere. Genome Res. 2003;13:182-194.

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    Suzuki A., Hori T., Nishino T., Usukura J., Miyagi A., Morikawa K., Fukagawa T. Spindle microtubules generate tension-dependent changes in the distribution of inner kinetochore proteins. J. Cell Biol. 2011;193:125-140.

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    Tachiwana H., Kagawa W., Shiga T., Osakabe A., Miya Y., Saito K., Hayashi-Takanaka Y., Oda T., Sato M., Park S.Y. Crystal structure of the human centromeric nucleosome containing CENP-A. Nature. 2011;476:232-235.

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    Takahashi K., Murakami S., Chikashige Y., Funabiki H., Niwa O., Yanagida M. A low copy number central sequence with strict symmetry and unusual chromatin structure in fission yeast centromere. Mol. Biol. Cell. 1992;3:819-835.

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    Takeuchi K., Nishino T., Mayanagi K., Horikoshi N., Osakabe A., Tachiwana H., Hori T., Kurumizaka H., Fukagawa T. The centromeric nucleosome-like CENP-T-W-S-X complex induces positive supercoils into DNA. Nucleic Acids Res. 2014;42:1644-1655.

    Not in our library10.1093/nar/gkt1124

  154. 154.

    Thakur J., Sanyal K. Efficient neocentromere formation is suppressed by gene conversion to maintain centromere function at native physical chromosomal loci in Candida albicans. Genome Res. 2013;23:638-652.

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    Vafa O., Sullivan K.F. Chromatin containing CENP-A and alpha-satellite DNA is a major component of the inner kinetochore plate. Curr. Biol. 1997;7:897-900.

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  156. 156.

    Van Hooser A.A., Ouspenski I.I., Gregson H.C., Starr D.A., Yen T.J., Goldberg M.L., Yokomori K., Earnshaw W.C., Sullivan K.F., Brinkley B.R. Specification of kinetochore-forming chromatin by the histone H3 variant CENP-A. J. Cell Sci. 2001;114:3529-3542.

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    Varma D., Wan X., Cheerambathur D., Gassmann R., Suzuki A., Lawrimore J., Desai A., Salmon E.D. Spindle assembly checkpoint proteins are positioned close to core microtubule attachment sites at kinetochores. J. Cell Biol. 2013;202:735-746.

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    Vissel B., Choo K.H. Human alpha satellite DNA—consensus sequence and conserved regions. Nucleic Acids Res. 1987;15:6751-6752.

    Not in our library10.1093/nar/15.16.6751

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    Vleugel M., Hoogendoorn E., Snel B., Kops G.J. Evolution and function of the mitotic checkpoint. Dev. Cell. 2012;23:239-250.

    Not in our library10.1016/j.devcel.2012.06.013

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    Volpe T.A., Kidner C., Hall I.M., Teng G., Grewal S.I., Martienssen R.A. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science. 2002;297:1833-1837.

    Not in our library10.1126/science.1074973

  161. 161.

    Voullaire L.E., Slater H.R., Petrovic V., Choo K.H. A functional marker centromere with no detectable alpha-satellite, satellite III, or CENP-B protein: activation of a latent centromere? Am. J. Hum. Genet. 1993;52:1153-1163.

    Not in our library

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    Wade C.M., Giulotto E., Sigurdsson S., Zoli M., Gnerre S., Imsland F., Lear T.L., Adelson D.L., Bailey E., Bellone R.R., Broad Institute Genome Sequencing Platform, Broad Institute Whole Genome Assembly Team. Genome sequence, comparative analysis, and population genetics of the domestic horse. Science. 2009;326:865-867.

    Not in our library10.1126/science.1178158

  163. 163.

    Wan X., O’Quinn R.P., Pierce H.L., Joglekar A.P., Gall W.E., DeLuca J.G., Carroll C.W., Liu S.T., Yen T.J., McEwen B.F. Protein architecture of the human kinetochore microtubule attachment site. Cell. 2009;137:672-684.

    Not in our library10.1016/j.cell.2009.03.035

  164. 164.

    Wang F., Dai J., Daum J.R., Niedzialkowska E., Banerjee B., Stukenberg P.T., Gorbsky G.J., Higgins J.M. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science. 2010;330:231-235.

    Not in our library10.1126/science.1189435

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    Warburton P.E., Cooke C.A., Bourassa S., Vafa O., Sullivan B.A., Stetten G., Gimelli G., Warburton D., Tyler-Smith C., Sullivan K.F. Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Curr. Biol. 1997;7:901-904.

    Not in our library10.1016/s0960-9822(06)00382-4

  166. 166.

    Watanabe Y. Sister chromatid cohesion along arms and at centromeres. Trends Genet. 2005;21:405-412.

    Not in our library10.1016/j.tig.2005.05.009

  167. 167.

    Waye J.S., Willard H.F. Human beta satellite DNA: genomic organization and sequence definition of a class of highly repetitive tandem DNA. Proc. Natl. Acad. Sci. USA. 1989;86:6250-6254.

    Not in our library10.1073/pnas.86.16.6250

  168. 168.

    Williams B.C., Murphy T.D., Goldberg M.L., Karpen G.H. Neocentromere activity of structurally acentric mini-chromosomes in Drosophila. Nat. Genet. 1998;18:30-37.

    Not in our library10.1038/ng0198-30

  169. 169.

    Williams J.S., Hayashi T., Yanagida M., Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin. Mol. Cell. 2009;33:287-298.

    Not in our library10.1016/j.molcel.2009.01.017

  170. 170.
    Imaging the fate of histone Cse4 reveals de novo replacement in S phase and subsequent stable residence at centromeres · 2014
    Not checked
  171. 171.

    Yamagishi Y., Sakuno T., Shimura M., Watanabe Y. Heterochromatin links to centromeric protection by recruiting shugoshin. Nature. 2008;455:251-255.

    Not in our library10.1038/nature07217

  172. 172.

    Yamagishi Y., Honda T., Tanno Y., Watanabe Y. Two histone marks establish the inner centromere and chromosome bi-orientation. Science. 2010;330:239-243.

    Not in our library10.1126/science.1194498

  173. 173.

    Yan Z., Delannoy M., Ling C., Daee D., Osman F., Muniandy P.A., Shen X., Oostra A.B., Du H., Steltenpool J. A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol. Cell. 2010;37:865-878.

    Not in our library10.1016/j.molcel.2010.01.039

  174. 174.
    Human centromere protein A (CENP-A) can replace histone H3 in nucleosome reconstitution in vitro · 2000
    Not checked
  175. 175.

    Zhang W., Colmenares S.U., Karpen G.H. Assembly of Drosophila centromeric nucleosomes requires CID dimerization. Mol. Cell. 2012;45:263-269.

    Not in our library10.1016/j.molcel.2011.12.010

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