Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage

Mol Cell. 2009 Aug 14;35(3):327-39. doi: 10.1016/j.molcel.2009.06.036.


Cdk2 and cdk1 are individually dispensable for cell-cycle progression in cancer cell lines because they are able to compensate for one another. However, shRNA-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated S phase cell-cycle arrest and the phosphorylation of a subset of ATR/ATM targets after DNA damage. Loss of DNA damage-induced checkpoint control was caused by a reduction in formation of BRCA1-containing foci. Mutation of BRCA1 at S1497 and S1189/S1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of BRCA1-containing foci. Abrogation of checkpoint control after cdk1 depletion or inhibition in non-small-cell lung cancer cells sensitized them to DNA-damaging agents. Conversely, reduced cdk1 activity caused more potent G2/M arrest in nontransformed cells and antagonized the response to subsequent DNA damage. Cdk1 inhibition may therefore selectively sensitize BRCA1-proficient cancer cells to DNA-damaging treatments by disrupting BRCA1 function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA1 Protein / physiology*
  • CDC2 Protein Kinase / metabolism
  • CDC2 Protein Kinase / physiology*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA Damage*
  • DNA Repair
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mutation
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • S Phase / physiology*
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism


  • BRCA1 Protein
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase