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BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage

Nature Genetics volume 30, pages 285–289 (2002)Cite this article

Abstract

The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain—a motif that is found in many proteins that are implicated in DNA damage response and in genome stability1. Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints2,3,4,5. Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage–induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase—proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm6. We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis.

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Figure 1: Expression of BRCA1 restores the G2/M checkpoint and regulates the expression and activity of checkpoint proteins.
Figure 2: BRCA1 alters the expression and localization of G2/M checkpoint proteins.
Figure 3: BRCA1 activates Chk1 kinase activity.
Figure 4: BRCA1 and Chk1 associate in vivo.
Figure 5: A model of the DNA damage checkpoint that integrates BRCA1.

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Acknowledgements

We thank Y. Pommier for the GST–Cdc25C plasmid, C. Smythe for the Chk2 antibody, Y. Shiloh for AT cells, S. Anderson and M. Kirby for flow cytometry, A. Dutra for help with confocal microscopy, E. Sausville and the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis at the National Cancer Institute for providing UCN-01; and P. Liu and S. Danoff for comments on the manuscript.

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  1. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ronit I. Yarden, Sherly Pardo-Reoyo & Lawrence C. Brody

  2. Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Magda Sgagias & Kenneth H. Cowan

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  1. Ronit I. Yarden
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Correspondence to Lawrence C. Brody.

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Yarden, R., Pardo-Reoyo, S., Sgagias, M. et al. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 30, 285–289 (2002). https://doi.org/10.1038/ng837

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