Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.

The DNA Damage Response (DDR) is a highly regulated cellular process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal influence between architectural features of damaged chromatin and signalling pathways that co-ordinate the DDR. However, the mechanisms governing such a relationship in response to DNA helix-distorting lesions, remain largely unexplored. Here, we show that stalling of RNA polymerase II at such lesions, induces local chromatin acetylation mediated primarily by the histone acetyltransferases p300 and PCAF. The resulting open chromatin stimulates dissociation from nascent RNA of late-stage, co-transcriptional spliceosomes and subsequent formation of RNA: DNA hybrids, leading to activation of ATM signalling. In turn, activated ATM modulates chromatin conformation by phosphorylating Histone H2A.X and stimulating p38MAPK/MSK1-dependent Histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as an integral part of the cellular response to transcription stress.