Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.
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.
Johnson
Neil
N
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cai
Dongpo
D
Kennedy
Richard D
RD
Pathania
Shailja
S
Arora
Mansi
M
Li
Yu-Chen
YC
D'Andrea
Alan D
AD
Parvin
Jeffrey D
JD
Shapiro
Geoffrey I
GI
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase
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