Biology subjects

Rodier, F.

Publications and source records attributed to Rodier, F..

3 recordsLinked to original sources

bioRxiv2018

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

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 re-entry 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.

cell biology↗

bioRxiv2018

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment \"in patient\" TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.\n\nOne Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer both in vitro and in patient.

cancer biology↗

bioRxiv2018

The NuA4 acetyltransferase and non-canonical chromatin-associated MRN/ATM activity temporally define senescence-associated secretory programs

Senescent cells display senescence-associated (SA) phenotypic programs such as proliferation arrest (SAPA) and secretory phenotype (SASP), which mediate their impact on tissue homeostasis. Curiously, senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but SASP requires days to develop, suggesting it requires additional molecular events. Here, we show that pDSBs provoke delayed recruitment of MRN/ATM and KAT5/TRRAP (NuA4/Tip60) complexes to global chromatin. This coincided with activating histone marks on up-regulated SASP genes, whereas depletion of these complexes compromised the SASP. Conversely, histone deacetylase inhibition triggered accelerated MRN/ATM/Tip60-dependent SASP without pDSBs, interlacing acetylation and non-canonical DNA damage-independent, low-level DDR activity in SASP maturation. DDR/acetylation regulation of SA programs is preserved in human cancer cells, suggesting novel targets for modifying treatment-induced SA phenotypes. We propose that delayed chromatin recruitment of acetyltransferases cooperates with non-canonical DDR signaling to ensure SASP activation only in the context of senescence, and not in response to a transient DNA damage-induced proliferation arrest.\n\nHIGHLIGHTS (4 MAX, 85 CHARACTERS EACH)-Tip60 complex cooperate with non-canonical DDR activity to trigger paracrine signals\n\n-Low-level chromatin-associated ATM activity is required for the SASP\n\n-The intensity and temporal dynamics of the SASP can be manipulated\n\neTOC blurb (40 words)A temporal ballet between DNA damage response ATM/MRN and NuA4/Tip60 complexes control senescence-associated paracrine signals that are important during aging and cancer therapy, suggesting that DNA damage responses, acetylation, and chromatin remodeling can be exploited to manipulate senescence and benefit health.

cell biology↗