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'origine | English |
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Pages (de-à) | 336-346 |
Nombre de pages | 11 |
Journal | Molecular Cell |
Volume | 65 |
Numéro de publication | 2 |
DOI | |
Statut de publication | Published - 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