Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence

Abstract

Loss of telomeric DNA leads to telomere uncapping, which triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Here, we show that in normal cells telomere uncapping triggers a focal telomeric DNA damage response accompanied by a transient cell cycle arrest. Subsequent cell division with dysfunctional telomeres resulted in sporadic telomeric sister chromatid fusions that gave rise to next-mitosis genome instability, including non-telomeric DNA lesions responsible for a stable, p53-mediated, senescence-associated proliferation arrest. Unexpectedly, the blocking of Rad51/RPA-mediated homologous recombination, but not non-homologous end joining (NHEJ), prevented senescence despite multiple dysfunctional telomeres. When cells approached natural replicative senescence, interphase senescent cells displayed genome instability, whereas near-senescent cells that underwent mitosis despite the presence of uncapped telomeres did not. This suggests that these near-senescent cells had not yet acquired irreversible telomeric fusions. We propose a new model for telomere-initiated senescence where tolerance of telomere uncapping eventually results in irreversible non-telomeric DNA lesions leading to stable senescence. Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability.

The multistep path to replicative senescence onset: zooming on triggering and inhibitory events at telomeric DNA

“…Frontiers in Cell and Developmental Biology frontiersin.org telomeres undergo HDR events that prevent a premature senescence onset by elongating telomeres, but, at the same time, as cells undergo subsequent cell divisions and arrests, genome instability increases. Accordingly, recent findings in human cells suggest that HDR might occur at uncapped telomeres and these events contribute to increase genome instability and promote senescence onset (Ghadaouia et al, 2018;Ghadaouia et al, 2021). Altogether these data suggest that HDR delays premature senescence onset, but at the same time it might promote genome instability and set the starting point for senescence onset.…”

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice

“…p53 is a transcription factor that mediates genome damage-induced senescence. Studies have shown that telomere DNA deletion [ 33 ], ionizing radiation [ 34 ], chemotherapy drugs [ 35 ] and other factors can trigger p53-mediated senescence process. As one of the transcriptional targets of p53, p21 is also a gene that regulates cell proliferation and cell senescence [ 36 ].…”

High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells

“…Other studies have also found that HDR can be deleterious when attempted near telomeres. HDR is involved in the sister chromatid fusions responsible for senescence in normal human cells with shortened telomeres ( 126 , 127 ). Similarly, HDR is involved in the generation of the branched DNA structures and extensive resection resulting in chromosome fusions in POT1-deficient cells ( 128 ).…”