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.