Coupling of Homologous Recombination and the Checkpoint by ATR.
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.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cyclin-Dependent Kinases, DNA Breaks, Double-Stranded, Fanconi Anemia Complementation Group N Protein, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein Binding, Recombinational DNA Repair, Signal Transduction, Time Factors, Tumor Suppressor Proteins
Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cyclin-Dependent Kinases, DNA Breaks, Double-Stranded, Fanconi Anemia Complementation Group N Protein, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein Binding, Recombinational DNA Repair, Signal Transduction, Time Factors, Tumor Suppressor Proteins
Mol. Cell
Date: Jan. 19, 2017
PubMed ID: 28089683
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