Telomeric dysfunction triggers an unstable growth arrest leading to irreparable genomic lesions and entry into cellular senescence

Abstract

Replicative senescence is the permanent growth arrest caused by gradual telomere attrition occurring at each round of genome replication. Critically shortened telomeres lose their protective shelterin complex and t-loop structure revealing uncapped chromosome ends that are recognized as DNA double-strand breaks causing a p53-dependent DNA damage response (DDR) towards proliferation arrest. Because telomeres are heterogeneous in length within a single cell, the number of short telomeres necessary for senescence onset remains ill defined.Using controlled Tin2-mediated shelterin inactivation, we show that telomere uncapping is not sufficient to trigger senescence. While uncapping generates expected telomeric DNA damage detection, the associated weak DDR allows a rapid bypass of the primary growth arrest and reentry into the cell cycle despite dysfunctional telomeres. During the ensuing mitosis, fused telomeres lead to additional DNA breaks and to genomic instability including chromosomes bridges or micronuclei, which sustain a secondary entry into stable growth arrest. The loss of p53 prevented both primary and secondary growth arrest, leading to amplified genomic instablility. Our results support a new multistep model for entry into telomere-mediated replicative senescence in normal cells, which is not directly induced by telomere uncapping, but rather by an amplification of DNA lesions caused by telomere fusions that leads to permanent irreparable genome damage.

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.…”

“…However, the frequency of transient arrests increases with ongoing cells divisions and telomere shortening, thus suggesting that short/dysfunctional telomeres contribute to reach the terminal arrest ( Figure 1 ). Interestingly, transient proliferation arrests preceding replicative senescence have been described in human cells too ( Ghadaouia et al, 2018 ; Ghadaouia et al, 2021 ).…”

“…Interestingly, genome instability increases upon subsequent non-terminal arrests both in yeast and in mammals ( Coutelier et al, 2018 ; Ghadaouia et al, 2018 ; Ghadaouia et al, 2021 ). An intriguing hypothesis suggests that dysfunctional telomeres are not direct inducers of replicative senescence, but they rather lead to a wider genome instability and a strong DDR activation that together trigger senescence onset ( Figure 1 ).…”

Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

“…Additionally, dysfunctional telomeres due to telomere uncapping can cause cellular senescence in an indirect manner. The unprotected telomeres undergo degradation ( Vodenicharov and Wellinger, 2006 ; Ghadaouia et al, 2018 ) and induce a weak DNA damage response (DDR). Unprotected telomeres are prone to chromosomal end fusion resulting in secondary DNA breaks and genomic instability, eliciting a strong DDR.…”

“…Unprotected telomeres are prone to chromosomal end fusion resulting in secondary DNA breaks and genomic instability, eliciting a strong DDR. Consequently, the additional DNA damage causes permanent growth arrest and cellular senescence ( Ghadaouia et al, 2018 ). Therefore, telomere length homeostasis must be maintained by telomere elongation to compensate for the end-replication problem and protect telomere ends.…”