Coupling of Homologous Recombination and the Checkpoint by ATR

Rémi Buisson, Joshi Niraj, Amélie Rodrigue, Chu Kwen Ho, Johannes Kreuzer, Tzeh Keong Foo, Emilie J.L. Hardy, Graham Dellaire, Wilhelm Haas, Bing Xia, Jean Yves Masson, Lee Zou

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143 Citations (Scopus)

Résumé

ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a “CDK-to-ATR switch” post-resection, directly coupling the checkpoint to HR.

Langue d'origineEnglish
Pages (de-à)336-346
Nombre de pages11
JournalMolecular Cell
Volume65
Numéro de publication2
DOI
Statut de publicationPublished - janv. 19 2017

Note bibliographique

Funding Information:
We thank the members of the L.Z. and Dyson labs for helpful discussions. R.B. is supported by a Marsha Rivkin Scholar Award and a Susan G. Komen Fellowship. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research and is supported by a Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.-Y.M. is an FRQS Chercheur National and FRQS Chair. This work is supported by grants from the NIH (GM076388 and CA197779 to L.Z.; CA138804 and CA188096 to B.X.), Federal Share of Program Income (to L.Z.), and CIHR (to J.-Y.M.).

Publisher Copyright:
© 2017 Elsevier Inc.

ASJC Scopus Subject Areas

  • Molecular Biology
  • Cell Biology

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