Coupling of Homologous Recombination and the Checkpoint by ATR

Mol Cell. 2017 Jan 19;65(2):336-346. doi: 10.1016/j.molcel.2016.12.007. Epub 2017 Jan 12.


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.

Keywords: ATR; BRCA1; CDK; PALB2; checkpoint; homologous recombination.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • DNA Breaks, Double-Stranded*
  • Fanconi Anemia Complementation Group N Protein
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Recombinational DNA Repair*
  • Signal Transduction
  • Time Factors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Cyclin-Dependent Kinases