title: Multiple genetic pathways regulate replicative senescence in telomerase-deficient yeast.
abstract: Most human tissues express low levels of telomerase and undergo telomere shortening and eventual senescence; the resulting limitation on tissue renewal can lead to a wide range of age-dependent pathophysiologies. Increasing evidence indicates that the decline in cell division capacity in cells that lack telomerase can be influenced by numerous genetic factors. Here, we use telomerase-defective strains of budding yeast to probe whether replicative senescence can be attenuated or accelerated by defects in factors previously implicated in handling of DNA termini. We show that the MRX (Mre11-Rad50-Xrs2) complex, as well as negative (Rif2) and positive (Tel1) regulators of this complex, comprise a single pathway that promotes replicative senescence, in a manner that recapitulates how these proteins modulate resection of DNA ends. In contrast, the Rad51 recombinase, which acts downstream of the MRX complex in double-strand break (DSB) repair, regulates replicative senescence through a separate pathway operating in opposition to the MRX-Tel1-Rif2 pathway. Moreover, defects in several additional proteins implicated in DSB repair (Rif1 and Sae2) confer only transient effects during early or late stages of replicative senescence, respectively, further suggesting that a simple analogy between DSBs and eroding telomeres is incomplete. These results indicate that the replicative capacity of telomerase-defective yeast is controlled by a network comprised of multiple pathways. It is likely that telomere shortening in telomerase-depleted human cells is similarly under a complex pattern of genetic control; mechanistic understanding of this process should provide crucial information regarding how human tissues age in response to telomere erosion.
authors.affiliation: Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.
authors.forename: Bari J
authors.initials: BJ
authors.lastname: Ballew
authors.forename: Victoria
authors.initials: V
authors.lastname: Lundblad
mesh_terms: D002455:Cell Division; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D004718:Saccharomycetales / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059506:Telomere Shortening; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C086930:RAD50 protein, S cerevisiae; C105362:RIF2 protein, S cerevisiae; C107849:SAE2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D034501:Telomere-Binding Proteins; C086929:XRS2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae
keywords: MRX; Rad51; Rif2; replicative senescence; telomerase; telomeres; yeast