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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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References

  1. Chen, Y., Lee, W. H. & Chew, H. K. Emerging roles of BRCA1 in transcriptional regulation and DNA repair. J. Cell. Physiol. 181, 385 –392 (1999).

    Article  CAS  Google Scholar 

  2. Welcsh, P. L., Owens, K. N. & King, M. C. Insights into the functions of BRCA1 and BRCA2. Trends Genet. 16, 69–74 (2000).

    Article  CAS  Google Scholar 

  3. Xu, X. et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 3, 389–395 ( 1999).

    Article  CAS  Google Scholar 

  4. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    Article  CAS  Google Scholar 

  5. Zhong, Q. et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285, 747– 750 (1999).

    Article  CAS  Google Scholar 

  6. Ouchi, T., Monteiro, A. N. A., August, A., Aaronson, S. A. & Hanafusa, H. BRCA1 regulates p53-dependent gene expression. Proc. Natl Acad. Sci.USA 95, 2302–2306 (1998).

    Article  ADS  CAS  Google Scholar 

  7. Somasundaram, K. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389, 187–190 (1997).

    Article  ADS  CAS  Google Scholar 

  8. Harkin, D. P. et al. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97, 575–586 (1999).

    Article  CAS  Google Scholar 

  9. Li, S. et al. Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 Is disrupted upon DNA damage. J. Biol. Chem. 274, 11334–11338 ( 1999).

    Article  CAS  Google Scholar 

  10. Wong, A. K. et al. Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17, 2279–2285 (1998).

    Article  CAS  Google Scholar 

  11. Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388– 25392 (1998).

    Article  CAS  Google Scholar 

  12. Schaeper, U., Subramanian, T., Lim, L., Boyd, J. M. & Chinnadurai, G. Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif. J. Biol. Chem. 273, 8549–8552 ( 1998).

    Article  CAS  Google Scholar 

  13. Shiloh, Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31, 635 –662 (1997).

    Article  CAS  Google Scholar 

  14. Smith, G. C. & Jackson, S. P. The DNA-dependent protein kinase. Genes Dev. 13, 916–934 (1999).

    Article  CAS  Google Scholar 

  15. Lees-Miller, S. P. et al. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science 267, 1183–1185 (1995).

    Article  ADS  CAS  Google Scholar 

  16. Ziv, Y. et al. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene 15, 159–167 (1997).

    Article  CAS  Google Scholar 

  17. Banin, S. et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674–1677 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677– 1679 (1998).

    Article  ADS  CAS  Google Scholar 

  19. Boyle, W. J., van der Geer, P. & Hunter, T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 201, 110–149 (1991).

    Article  CAS  Google Scholar 

  20. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162– 1166 (1999).

    Article  CAS  Google Scholar 

  21. Kastan, M. B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    Article  CAS  Google Scholar 

  22. Khosravi, R. et al. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 14973–14977 (1999).

    Article  ADS  CAS  Google Scholar 

  23. Lavin, M. Role of the ataxia-telangiectasia gene (ATM) in breast cancer. A-T heterozygotes seem to have an increased risk but its size is unknown. Br. Med. J. 317, 486–487 ( 1998).

    Article  CAS  Google Scholar 

  24. Swift, M. & Su, Y. Link between breast cancer and ATM gene is strong. Br. Med. J. 318, 400 (1999).

    Article  CAS  Google Scholar 

  25. Li, S. et al. Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J. Biol. Chem. 273, 6183–6189 (1998).

    Article  CAS  Google Scholar 

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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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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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