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Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response

Nature volume 406, pages 210–215 (2000)Cite this article

Abstract

BRCA1 encodes a familial breast cancer suppressor that has a critical role in cellular responses to DNA damage1,2. Mouse cells deficient for Brca1 show genetic instability, defective G2–M checkpoint control and reduced homologous recombination3,4. BRCA1 also directly interacts with proteins of the DNA repair machinery5 and regulates expression of both the p21 and GADD45 genes6,7,8. However, it remains unclear how DNA damage signals are transmitted to modulate the repair function of BRCA1. Here we show that the BRCA1-associated protein CtIP9,10,11,12 becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia13. ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.

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Figure 1: IR-induced phosphorylation of CtIP is ATM dependent.
Figure 2: Identification of ATM phosphorylation sites on CtIP.
Figure 3: Phosphorylation of CtIP by ATM is essential for dissociation of CtIP from BRCA1 upon IR.
Figure 4: Regulation of GADD45 expression by BRCA1, CtIP and CtBP.
Figure 5: Model showing how ATM modulates the BRCA1 transcriptional regulation of DNA damage-response genes following IR.

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Acknowledgements

We thank D. A. Haber for the pI-3 plasmid, T. Subramanian and G. Chinnadurai for the pRc-CMV–CtBP plasmid, and J. Allalunis-Turner for the M059J/K cells. We also thank S. P. Lees-Miller for advice, P. Garza and D. Jones for antibody production, S.-C. J. Lin and M.-J. Chen for constructing ATM plasmids, and T. Boyer for critical reading. This study is supported by NIH (grants to W.-H.L., P.-L.C. and E.L.); and from the US Department of Defense (grants to N.T. and predoctoral training support to S.L and L.Z).

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  1. Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, 78245, Texas, USA

    Shang Li, Nicholas S. Y. Ting, Lei Zheng, Phang-Lang Chen, Eva Y.-H. P. Lee & Wen-Hwa Lee

  2. Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel

    Yael Ziv & Yosef Shiloh

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  1. Shang Li
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Correspondence to Wen-Hwa Lee.

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Li, S., Ting, N., Zheng, L. et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406, 210–215 (2000). https://doi.org/10.1038/35018134

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