How DNA double-strand breaks (DSBs) are sensed and signaled to promote checkpoint activation and DNA repair has remained elusive. In mammalian cells, the checkpoint kinase ATM is recruited to DSBs through association with the Mre11–Rad50–Nbs1 complex and activates downstream components of the DNA-damage response (DDR). Now, work by Kaidi and Jackson reveals how damage-induced chromatin modifications regulate ATM activity. They show that the lysine acetyltransferase KAT5, previously known to acetylate and stimulate ATM, is itself phosphorylated in cells exposed to ionizing radiation. The modified residue, Tyr44, is within the chromodomain that mediates KAT5 interaction with trimethylated histone H3 Lys9 (H3K9me3) and other chromatin marks, and its phosphorylation enhances both chromatin binding affinity and ATM acetylation activity. H3K9me3 peptides stimulate ATM acetylation by KAT5 in vitro, and Tyr44 mutations that prevent phosphorylation impair ATM-induced checkpoint activation in vivo, rendering cells hypersensitive to ionizing radiation. In contrast, Tyr44 mutation does not affect KAT5's transcriptional activation functions, thus suggesting that Tyr44 phosphorylation is required for DDR signaling. The role of chromatin structure in KAT5-mediated ATM induction is examined by monitoring the effect of increasing cellular histone acetylation levels by TSA treatment or by HP1 depletion to expose H3K9me3. Remarkably, both conditions induce Tyr44 phosphorylation and KAT5 chromatin retention to promote ATM acetylation and phosphorylation of ATM substrates in the absence of DSBs. These observations suggest that KAT5 and ATM may also function in a genome surveillance pathway signaling repair in response to chromatin alterations. Lastly, inhibition or depletion of the tyrosine kinase c-Abl abolishes both KAT5 Tyr44 phosphorylation and ATM-dependent cell-cycle arrest, thus explaining previous observations linking c-Abl and the ionizing radiation-induced checkpoint response. This work provides crucial molecular insights into how chromatin changes are read and interpreted by cellular signaling pathways. (Nature 498, 70–74, 2013)