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hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response

Nature volume 404, pages 201–204 (2000)Cite this article

Abstract

Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer2,3. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair4,5,6,7 and cell-cycle checkpoint8,9,10. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage11,12. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family13,14,15,16,17,18,19,20. Here we report that the human Cds1 kinase (hCds1/Chk2)21,22,23 regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.

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Figure 1: Cds1 phosphorylates Ser 988 of BRCA1 in vitro.
Figure 2: Cds1 phosphorylates Ser 988 of human BRCA1 in vivo.
Figure 3: Cds1 and BRCA1 are localized to overlapping nuclear foci.
Figure 4: BRCA1–hCds1 interaction is sensitive to DNA damage.
Figure 5: Phosphorylation of Ser 988 is important for BRCA1 function.

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Acknowledgements

We thank D. Livingston and R. Scully for the BRCA1 plasmids; Y. Shiloh for the AT cells; M. Kirby for flow cytometry; and Y. Xu and C. Combs for help with confocal microscopy. We also thank W. S. Lane, D. P. Kirby and K. A. Pierce of the Harvard Microchemistry facility for expertise in tandem mass spectrometry peptide sequencing.

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  1. Laboratory of Molecular Hematology, NHLBI, NIH, Bethesda , 20892, Maryland, USA

    Jong-Soo Lee, Kimberly M. Collins, Alexandra L. Brown, Chang-Hun Lee & Jay H. Chung

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  1. Jong-Soo Lee
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Correspondence to Jay H. Chung.

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Lee, JS., Collins, K., Brown, A. et al. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response . Nature 404, 201–204 (2000). https://doi.org/10.1038/35004614

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