ATM signalling facilitates repair of DNA double strand breaks associated with heterochromatin

ATM-signalling is essential for the repair of a subset of DNA double strand breaks (DSBs); however its precise role in DSB-repair is unclear. Here, we show that no more than ~25% of DSBs require ATM-signalling for repair and this correlates with increased chromatin complexity but not damage complexity. Importantly, we demonstrate that heterochromatic DSBs are generally repaired more slowly than euchromatic DSBs and that ATM-signalling is specifically required for DSB-repair within heterochromatin. Significantly, knockdown of the transcriptional repressor KAP-1, an ATM substrate, or the heterochromatin-building factors HP1 or HDAC1/2 alleviates the requirement for ATM in DSB-repair. We propose that ATM signalling temporarily perturbs heterochromatin via KAP-1 and that this is critical for DSB-repair/processing within otherwise compacted/inflexible chromatin. In support of this, ATM-signalling alters KAP-1 affinity for chromatin enriched for heterochromatic factors. These data suggest that the importance of ATM-signalling for DSB-repair increases as the heterochromatic component of a genome expands.