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

N. Johnson, D. Cal, Richard Kennedy, S. Pathania, M. Arora, Y. Li, A.D. D\'Andrea, J.D. Parvin, G.I. Shapiro

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)327-339
Number of pages13
JournalMolecular Cell
Volume35
Issue number3
DOIs
Publication statusPublished - 14 Aug 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Johnson, N., Cal, D., Kennedy, R., Pathania, S., Arora, M., Li, Y., D\'Andrea, A. D., Parvin, J. D., & Shapiro, G. I. (2009). Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Molecular Cell, 35(3), 327-339. https://doi.org/10.1016/j.molcel.2009.06.036