Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins

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.

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ACKNOWLEDGMENTS

We thank past and present members of the Blackburn laboratory for critical discussions. We thank Shivani Nautiyal for providing information on experimental results obtained in the Blackburn laboratory prior to the experiments reported in this paper and for valuable critical input and discussions.

We report no conflicts of interest.

E.H.B. acknowledges support from the NIH (grant GM026259). K.A.J. acknowledges support from his training grant (T32-GM007810).

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.