Cellular senescence induces replication stress without affecting DNA replication timing
Le résumé fourni par la source
Organismal aging entails a gradual decline of normal physiological functions and a major contributor to this decline is withdrawal of the cell cycle, known as senescence. Senescence can result from telomere diminution leading to a finite number of population doublings, known as replicative senescence, or from oncogene overexpression, as a protective mechanism against cancer. Senescence is associated with large-scale chromatin re-organization and changes in gene expression. Replication stress is a complex phenomenon, defined as the slowing or stalling of replication fork progression and/or DNA synthesis, which has serious implications for genome stability, and consequently in human diseases. Aberrant replication fork structures activate the replication stress response leading to the activation of dormant origins, which is thought to be a safeguard mechanism to complete DNA replication on place and time. However, the relationship between replicative stress and the changes in the spatiotemporal program of DNA replication in senescence progression remains unclear. To investigate the relationship between replication stress and senescence, we studied the DNA replication program during senescence progression, in proliferative and pre-senescent cells from donors of various ages, by single DNA fiber combing of replicated DNA, origin mapping by sequencing short nascent strands and genome-wide profiling of replication timing. We demonstrate that, progression into replicative senescence leads to reduced replication fork rates and activation of dormant origins, which are the hallmarks of replication stress. However, with the exception of a delay in replication timing of the CREB5 gene in all pre-senescent cells, replication timing was unaffected by replication stress during entry into either oncogene-induced or replicative senescence. Consequently, we conclude that replication timing alterations associated with physiological and accelerated aging, do not result from senescence progression. Our results clarify the interplay between senescence, aging and replication programs and demonstrate that replication timing is largely resistant to replication stress.
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