Homo sapiens Transcriptome or Gene expression

In response to DNA damage tissue homoeostasis is ensured by elaborate protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage-response signaling pathways coordinate these processes, in part, by propagating gene expression-modulating signals. DNA damage does not only influence abundance of mRNAs, but also their coding information through alternative splicing. This level of regulation is thus far poorly understood. Here we show that transcription-blocking DNA lesions promote displacement of activated spliceosomes and initiate a positive feedback loop centered on the DNA damage signaling kinase ATM. Pausing of elongating RNA polymerase at DNA lesions induces spliceosome displacement and R-loop formation. This in turn activates ATM, which signals to further impede splicing activity. These findings define the R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells and highlight a key role for spliceosome displacement in this process.