Journal
MOLECULAR CELL
Volume 65, Issue 2, Pages 336-346Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.12.007
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Funding
- Marsha Rivkin Scholar Award
- Susan G. Komen Fellowship
- Jim and Ann Orr Massachusetts General Hospital Research Scholar Award
- NIH [GM076388, CA197779, CA138804, CA188096]
- Federal Share of Program Income
- CIHR
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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 CDKto-ATR switch'' post-resection, directly coupling the checkpoint to HR.
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