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  • Non-canonical ATM/MRN activities temporally define the senescence secretory program.

Non-canonical ATM/MRN activities temporally define the senescence secretory program.

EMBO reports (2020-08-14)
Nicolas Malaquin, Marc-Alexandre Olivier, Aurélie Martinez, Stéphanie Nadeau, Christina Sawchyn, Jean-Philippe Coppé, Guillaume Cardin, Frédérick A Mallette, Judith Campisi, Francis Rodier
ABSTRACT

Senescent cells display senescence-associated (SA) phenotypic programs such as stable proliferation arrest (SAPA) and a secretory phenotype (SASP). Senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but the SASP requires days to develop. Here, we show that following the immediate canonical DDR, a delayed chromatin accumulation of the ATM and MRN complexes coincides with the expression of SASP factors. Importantly, histone deacetylase inhibitors (HDACi) trigger SAPA and SASP in the absence of DNA damage. However, HDACi-induced SASP also requires ATM/MRN activities and causes their accumulation on chromatin, revealing a DNA damage-independent, non-canonical DDR activity that underlies SASP maturation. This non-canonical DDR is required for the recruitment of the transcription factor NF-κB on chromatin but not for its nuclear translocation. Non-canonical DDR further does not require ATM kinase activity, suggesting structural ATM functions. We propose that delayed chromatin recruitment of SASP modulators is the result of non-canonical DDR signaling that ensures SASP activation only in the context of senescence and not in response to transient DNA damage-induced proliferation arrest.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Fibronectin bovine plasma, solution, sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder
Sigma-Aldrich
Lactate Assay Kit, sufficient for 100 colorimetric or fluorometric tests
Sigma-Aldrich
Thapsigargin, ≥98% (HPLC), solid film