Repression of transcription at DNA breaks requires cohesin throughout interphase and prevents genome instability

Meisenberg, Cornelia, Pinder, Sarah I, Hopkins, Suzanna R, Wooller, Sarah K, Benstead-Hume, Graeme, Pearl, Frances M G, Jeggo, Penny A and Downs, Jessica A (2019) Repression of transcription at DNA breaks requires cohesin throughout interphase and prevents genome instability. Molecular Cell. ISSN 1097-2765

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Abstract

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.

Item Type: Article
Keywords: DNA repair, DNA damage, transcription, genomic instability
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Biology and Environmental Science
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Penny Jeggo
Date Deposited: 18 Dec 2018 11:21
Last Modified: 18 Dec 2018 11:22
URI: http://sro.sussex.ac.uk/id/eprint/80808

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Project NameSussex Project NumberFunderFunder Ref
UnsetMR/N02155X/1Medical Research CouncilUnset