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

journal contribution
posted on 2023-06-09, 16:16 authored by Cornelia Meisenberg, Sarah I Pinder, Suzanna R Hopkins, Sarah Wooller, Graeme Benstead-Hume, Frances PearlFrances Pearl, Penny Jeggo, Jessica A Downs
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.

Funding

MR/N02155X/1; Medical Research Council

History

Publication status

  • Published

File Version

  • Published version

Journal

Molecular Cell

ISSN

1097-2765

Publisher

Elsevier

Issue

2

Volume

73

Page range

212-223.e7

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-12-18

First Open Access (FOA) Date

2018-12-18

First Compliant Deposit (FCD) Date

2018-12-14

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