Identification of >150 novel genes that affect telomere length and discovery of a link between vitamin B6 salvage and telomere metabolism
Abstract (Summary)The nucleoprotein structures at the end of chromosomes, called telomeres, have many functions important for maintaining genomic integrity. They provide end-protection, limit cellular proliferation, regulate sub-telomeric gene expression, help in chromosome positioning, and aid homolog pairing in meiosis. Generally, telomeric DNA is composed of tandem arrays of a simple repeat. A reverse transcriptase enzyme complex, telomerase, can add telomeric repeats to 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 growth arrest. Proper length maintenance of telomeres is central to all their functions. This requires coordinated action of many proteins. In order to broaden our knowledge about the mechanisms that control telomere length, we systematically examined ~4800 haploid deletion mutants of Saccharomyces cerevisiae for telomere length defects. We identified more than 150 candidate genes not previously known to affect telomere length. Many of these genes have known functions in diverse cellular processes ranging from chromatin remodeling and DNA metabolism to vesicular trafficking and mitochondrial and ribosomal structure and organization. Among the 109 that showed consistently shorter telomere lengths upon growth on rich medium were deletions of a putative pyridoxal (vitamin B6) kinase, bud16?, and pyridoxine/pyridoxamine phosphate oxidase, pdx3?. This finding suggested a possible connection between vitamin B6 metabolism and telomere length maintenance. Yeast can generate the active form of vitamin B6 by de novo synthesis or by salvaging precursor vitamers. We demonstrate that BUD16 and PDX3 encode the bona fide kinase and oxidase of the vitamin B6 salvage pathway and are not required for biosynthesis. Our experiments have helped characterize the salvage pathway in yeast and show that the short telomere phenotypes in bud16? and pdx3? are due to B6 deficiency. The mechanism by which B6 deficiency affects telomere length remains unclear.
School:The University of Georgia
School Location:USA - Georgia
Source Type:Master's Thesis
Date of Publication: