Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability

Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer. [Display omitted] •Cohesin and PBAF repress gene transcription near DNA double-strand breaks (DSBs)•Transcriptional repression at DSBs requires cohesin and PBAF throughout interphase•Loss of DSB-induced gene repression leads to more large-scale genome alterations Meisenberg et al. show that, in response to DNA double strand breaks (DSBs), cohesin is required to repress nearby transcription. This happens throughout interphase, regardless of whether a sister chromatid is present. Failure to repress transcription near a DNA DSB results in an increase in large-scale chromosome rearrangements.