Abstract
Telomeres cap the ends of chromosomes, protecting them from degradation and inappropriate DNA repair processes that can lead to genomic instability. A short telomere elicits increased telomerase action on itself that replenishes telomere length, thereby stabilizing the telomere. In the prolonged absence of telomerase activity in dividing cells, telomeres eventually become critically short, inducing a permanent cell cycle arrest (senescence). We recently showed that even early after telomerase inactivation (ETI), yeast cells have accelerated mother cell aging and mildly perturbed cell cycles. Here, we show that the complete disruption of DNA damage response (DDR) adaptor proteins in ETI cells causes severe growth defects. This synthetic-lethality phenotype was as pronounced as that caused by extensive DNA damage in wild-type cells but showed genetic dependencies distinct from such damage and was completely alleviated by SML1 deletion, which increases deoxynucleoside triphosphate (dNTP) pools. Our results indicated that these deleterious effects in ETI cells cannot be accounted for solely by the slow erosion of telomeres due to incomplete replication that leads to senescence. We propose that normally occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in two parallel pathways and that deletion of Sml1 prevents this stress.
Highlights
Telomeres are composed of repetitive DNA sequences and their bound protective proteins at the ends of linear eukaryotic chromosomes
We previously reported that individual early after telomerase inactivation (ETI) yeast mother cells displayed a reduction in mother cell life span and greater heterogeneity of cell cycle durations than the WT [35]
Mutations in one half of the DNA damage response (DDR) exacerbated the cell cycle and accelerated mother cell aging phenotypes observed in ETI cells, while mutations in the other half of the pathway had little to no effect
Summary
Telomeres are composed of repetitive DNA sequences and their bound protective proteins at the ends of linear eukaryotic chromosomes. Following a mutation inactivating telomerase, yeast cells can continue cycling for approximately 60 to 80 divisions before their telomeres become critically short and can no longer maintain the protective complement of proteins At this point, here referred to as late after telomerase inactivation (LTI), the telomere becomes deprotected and activates a Mec1-dependent DNA damage response (DDR), leading to a permanent cell cycle arrest known as senescence. DNA damage signaling in budding yeast is primarily initiated by two upstream phosphatidylinositol 3-kinase (PI3K)-related kinases, Mec and Tel1 [17] In addition to their functions in the DDR, in telomerase wild-type (WT) cells, Mec and Tel have a slight and a major role, respectively, in telomere length regulation, and cells lacking both kinases senesce as if they did not have active telomerase [18].
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