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RASSF1A–LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2

Pefani, Dafni-Eleftheria; Latusek, Robert; Pires, Isabel; Grawenda, Anna M.; Yee, Karen S.; Hamilton, Garth; van der Weyden, Louise; Esashi, Fumiko; Hammond, Ester M.; O'Neill, Eric

Authors

Dafni-Eleftheria Pefani

Robert Latusek

Isabel Pires

Anna M. Grawenda

Karen S. Yee

Garth Hamilton

Louise van der Weyden

Fumiko Esashi

Ester M. Hammond

Eric O'Neill



Abstract

Genomic instability is a key hallmark of cancer leading to tumour heterogeneity and therapeutic resistance. ​BRCA2 has a fundamental role in error-free DNA repair but also sustains genome integrity by promoting ​RAD51 nucleofilament formation at stalled replication forks. ​CDK2 phosphorylates ​BRCA2 (pS3291-​BRCA2) to limit stabilizing contacts with polymerized ​RAD51; however, how replication stress modulates ​CDK2 activity and whether loss of pS3291-​BRCA2 regulation results in genomic instability of tumours are not known. Here we demonstrate that the Hippo pathway kinase ​LATS1 interacts with ​CDK2 in response to genotoxic stress to constrain pS3291-​BRCA2 and support ​RAD51 nucleofilaments, thereby maintaining genomic fidelity during replication stalling. We also show that ​LATS1 forms part of an ​ATR-mediated response to replication stress that requires the tumour suppressor ​RASSF1A. Importantly, perturbation of the ​ATR–​RASSF1A–​LATS1 signalling axis leads to genomic defects associated with loss of ​BRCA2 function and contributes to genomic instability and ‘BRCA-ness’ in lung cancers.

Citation

Pefani, D.-E., Latusek, R., Pires, I., Grawenda, A. M., Yee, K. S., Hamilton, G., van der Weyden, L., Esashi, F., Hammond, E. M., & O'Neill, E. (2014). RASSF1A–LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. Nature Cell Biology, 16(10), 962-971. https://doi.org/10.1038/ncb3035

Acceptance Date Aug 5, 2014
Online Publication Date Sep 14, 2014
Publication Date 2014-10
Deposit Date Mar 14, 2016
Publicly Available Date Nov 23, 2017
Journal Nature cell biology
Print ISSN 1465-7392
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 16
Issue 10
Pages 962-971
DOI https://doi.org/10.1038/ncb3035
Keywords Cell signalling; DNA damage and repair; DNA replication
Public URL https://hull-repository.worktribe.com/output/471889
Publisher URL http://www.nature.com/ncb/journal/v16/n10/abs/ncb3035.html
Additional Information Author's accepted manuscript of article published in: Nature cell biology, 2014, v.16, issue 10
Contract Date Nov 23, 2017

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