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

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. Synopsis Expression of SASP factors requires a non‐canonical function of the DNA damage response (DDR) activated in senescent cells, which is characterized by an accumulation of ATM and MRN complexes on chromatin, independent of the presence of DNA DSBs. HDAC inhibitors induce senescence, a non‐canonical DDR, and an ATM/MRN‐dependent SASP in the absence of DNA damage. The non‐canonical DDR enhances the binding of NF‐κB to chromatin. The kinase activity of ATM is not required in the non‐canonical DDR. Graphical Abstract Expression of SASP factors requires a non‐canonical function of the DNA damage response (DDR) activated in senescent cells, which is characterized by an accumulation of ATM and MRN complexes on chromatin, independent of the presence of DNA DSBs.