Molecular Cell
Volume 35, Issue 3, 14 August 2009, Pages 327-339
Journal home page for Molecular Cell

Article
Cdk1 Participates in BRCA1-Dependent S Phase Checkpoint Control in Response to DNA Damage

https://doi.org/10.1016/j.molcel.2009.06.036Get rights and content
Under an Elsevier user license
open archive

Summary

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.

CELLCYCLE
DNA
SIGNALING

Cited by (0)

8

Present address: Almac Diagnostics Ltd., Craigavon BT63 5QD, UK