Identification of >150 novel genes that affect telomere length and discovery of a link between vitamin B6 salvage and telomere metabolism
Askree, Syed Hussain Mehdi
MetadataShow full item record
The nucleoprotein structures at the end of chromosomes, called telomeres, have manyfunctions important for maintaining genomic integrity. They provide end-protection, limitcellular proliferation, regulate sub-telomeric gene expression, help in chromosome positioning,and aid homolog pairing in meiosis. Generally, telomeric DNA is composed of tandem arrays ofa simple repeat. A reverse transcriptase enzyme complex, telomerase, can add telomeric repeatsto the ends. In the absence of telomerase expression, as in the case of most human somatic cells,telomeres shorten with each cell division, and this sequence loss eventually triggers growtharrest. Proper length maintenance of telomeres is central to all their functions. This requirescoordinated action of many proteins. In order to broaden our knowledge about the mechanismsthat control telomere length, we systematically examined ~4800 haploid deletion mutants ofSaccharomyces cerevisiae for telomere length defects. We identified more than 150 candidategenes not previously known to affect telomere length. Many of these genes have knownfunctions in diverse cellular processes ranging from chromatin remodeling and DNA metabolismto vesicular trafficking and mitochondrial and ribosomal structure and organization. Among the109 that showed consistently shorter telomere lengths upon growth on rich medium weredeletions of a putative pyridoxal (vitamin B6) kinase, bud16 , and pyridoxine/pyridoxaminephosphate oxidase, pdx3 . This finding suggested a possible connection between vitamin B6metabolism and telomere length maintenance. Yeast can generate the active form of vitamin B6by de novo synthesis or by salvaging precursor vitamers. We demonstrate that BUD16 and PDX3encode the bona fide kinase and oxidase of the vitamin B6 salvage pathway and are not requiredfor biosynthesis. Our experiments have helped characterize the salvage pathway in yeast andshow that the short telomere phenotypes in bud16 and pdx3 are due to B6 deficiency. Themechanism by which B6 deficiency affects telomere length remains unclear.