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首页> 外文期刊>Molecular and Cellular Biology >Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins
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Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins

机译：酵母中端粒酶作用的早期丧失产生了对DNA损伤反应衔接蛋白的依赖

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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.
机译：端粒位于染色体末端，可保护它们免于降解和不适当的DNA修复过程（可能导致基因组不稳定）。端粒短会引起自身的端粒酶作用增强，从而补充端粒的长度，从而稳定端粒。在分裂细胞中长期缺乏端粒酶活性的情况下，端粒最终变得非常短，导致永久性细胞周期停滞（衰老）。我们最近显示，即使在端粒酶失活（ETI）早期，酵母细胞仍会加速母细胞衰老并轻度扰动细胞周期。在这里，我们显示ETI细胞中的DNA损伤反应（DDR）适配器蛋白的完全破坏会导致严重的生长缺陷。这种合成致死性表型与野生型细胞中广泛的DNA损伤所引起的显着性相同，但显示出与此类损伤不同的遗传依赖性，并且被SML1缺失完全缓解，SML1缺失增加了脱氧核苷三磷酸（dNTP）库。我们的结果表明，由于复制不完全导致衰老，端粒的缓慢侵蚀不能完全解释ETI细胞中的这些有害作用。我们提出正常发生的端粒DNA复制压​​力可以通过端粒酶活性和DDR在两个平行途径中解决，而Sml1的缺失可以防止这种压力。

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