Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of <it>sel-12 </it>mutants with amber stop mutations in <it>Caenorhabditis elegans</it>

<p>Abstract</p> <p>Background</p> <p>Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the <it>Caenorhabditis elegans sel-12 </it>presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the <it>lin-12</it>/Notch receptor. Mutations in six <it>spr </it>genes (for suppressor of presenilin) are known to strongly suppress <it>sel-12</it>. Mutations in most strong <it>spr </it>genes suppress <it>sel-12 </it>by de-repressing the transcription of the largely functionally equivalent <it>hop-1 </it>presenilin gene. However, how mutations in the <it>spr-2 </it>gene suppress <it>sel-12 </it>is unknown.</p> <p>Results</p> <p>We show that <it>spr-2 </it>mutations increase the levels of <it>sel-12 </it>transcripts with Premature translation Termination Codons (PTCs) in embryos and L1 larvae. mRNA transcripts from <it>sel-12 </it>alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD). However, <it>spr-2 </it>mutations do not appear to affect NMD. Mutations in the <it>smg </it>genes, which are required for NMD, can restore <it>sel-12(PTC) </it>transcript levels and ameliorate the phenotype of <it>sel-12 </it>mutants with amber PTCs. However, the phenotypic suppression of <it>sel-12 </it>by <it>smg </it>genes is nowhere near as strong as the effect of previously characterized <it>spr </it>mutations including <it>spr-2</it>. Consistent with this, we have identified only two mutations in <it>smg </it>genes among the more than 100 <it>spr </it>mutations recovered in genetic screens.</p> <p>Conclusion</p> <p><it>spr-2 </it>mutations do not suppress <it>sel-12 </it>by affecting NMD of <it>sel-12(PTC) </it>transcripts and appear to have a novel mechanism of suppression. The fact that mutations in <it>smg </it>genes can ameliorate the phenotype of <it>sel-12 </it>alleles with amber PTCs suggests that some read-through of <it>sel-12(amber) </it>alleles occurs in <it>smg </it>backgrounds.</p>

Abstract licence: CC BY

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.