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Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway

Oncogene volume 32, pages 1943–1949 (2013)Cite this article

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Abstract

Brca1 deficiency leads to the development of breast cancer. We previously found that Brca1 deficiency activates the Akt oncogenic pathway. Reduced expression of Brca1 was highly correlated with increased activated Akt in human breast cancer samples. Furthermore, activation of Akt1 was involved in Brca1-deficiency-mediated tumorigenesis in mice. Defective homologous recombination (HR) is thought to be a major contributor to tumorigenesis in Brca1 deficiency. Here, we show that Akt1 promotes chromosome instability in Brca1-deficent cells. DNA breaks in Brca1-deficent cells are aberrantly joined into complex chromosome rearrangements by a process dependent on Akt1. Depletion of Akt1 increases HR in Brca1-mutant cells, which is rescued by expression of wild-type, but not mutant Akt1 with deletion of Brca1-binding domain. Mechanistically, activated Akt1 in Brca1-deficient cells impairs Chk1 nuclear localization and subsequently disrupts interaction of Chk1 and Rad51 leading to HR defects. Our results indicate that Brca1 deficiency might activate Akt1 contributing to tumorigenesis through regulation of the Chk1-Rad51 signaling.

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References

  1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.

    Article  CAS  Google Scholar 

  2. Yu X, Chini CC, He M, Mer G, Chen J . The BRCT domain is a phospho-protein binding domain. Science 2003; 302: 639–642.

    Article  CAS  Google Scholar 

  3. Ludwig T, Fisher P, Ganesan S, Efstratiadis A . Tumorigenesis in mice carrying a truncating Brca1 mutation. Genes Dev 2001; 15: 1188–1193.

    Article  CAS  Google Scholar 

  4. Manke IA, Lowery DM, Nguyen A, Yaffe MB . BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 2003; 302: 636–639.

    Article  CAS  Google Scholar 

  5. Deng CX . BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res 2006; 34: 1416–1426.

    Article  CAS  Google Scholar 

  6. Bellacosa A, Kumar CC, Di CA, Testa JR . Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005; 94: 29–86.

    Article  CAS  Google Scholar 

  7. Xiang T, Jia Y, Sherris D, Li S, Wang H, Lu D et al. Targeting the Akt/mTOR pathway in Brca1-deficient cancers. Oncogene 2011; 30: 2443–2450.

    Article  CAS  Google Scholar 

  8. Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN et al. Negative regulation of AKT activation by BRCA1. Cancer Res 2008; 68: 10040–10044.

    Article  CAS  Google Scholar 

  9. Moynahan ME, Chiu JW, Koller BH, Jasin M . Brca1 controls homology-directed DNA repair. Mol Cell 1999; 4: 511–518.

    Article  CAS  Google Scholar 

  10. Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM . Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell 1999; 4: 1093–1099.

    Article  CAS  Google Scholar 

  11. Plo I, Laulier C, Gauthier L, Lebrun F, Calvo F, Lopez BS . AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51. Cancer Res 2008; 68: 9404–9412.

    Article  CAS  Google Scholar 

  12. Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 2001; 28: 266–271.

    Article  CAS  Google Scholar 

  13. Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010; 141: 243–254.

    Article  CAS  Google Scholar 

  14. Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997; 88: 265–275.

    Article  CAS  Google Scholar 

  15. Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK . The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 2000; 275: 23899–23903.

    Article  CAS  Google Scholar 

  16. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der GH et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 2010; 17: 688–695.

    Article  CAS  Google Scholar 

  17. Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD et al. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc Natl Acad Sci USA 2005; 102: 1110–1115.

    Article  CAS  Google Scholar 

  18. Sorensen CS, Hansen LT, Dziegielewski J, Syljuasen RG, Lundin C, Bartek J et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 2005; 7: 195–201.

    Article  CAS  Google Scholar 

  19. Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005; 7: 193–204.

    Article  CAS  Google Scholar 

  20. Deng CX . Tumor formation in Brca1 conditional mutant mice. Environ Mol Mutagen 2002; 39: 171–177.

    Article  CAS  Google Scholar 

  21. Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 1999; 22: 37–43.

    Article  CAS  Google Scholar 

  22. Yang Q, Zheng YL, POT1 Harris CC . and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 2005; 25: 1070–1080.

    Article  CAS  Google Scholar 

  23. Zeng S, Xiang T, Pandita TK, Gonzalez-Suarez I, Gonzalo S, Harris CC et al. Telomere recombination requires the MUS81 endonuclease. Nat Cell Biol 2009; 11: 616–623.

    Article  CAS  Google Scholar 

  24. Yang Q, Zhang R, Wang XW, Linke SP, Sengupta S, Hickson ID et al. The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. Oncogene 2004; 23: 3749–3756.

    Article  CAS  Google Scholar 

  25. Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D et al. The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. J Biol Chem 2002; 277: 31980–31987.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Chuxia Deng for providing the Brca1WT and Brca1Δ11/Δ11 MEFs. We thank Buck Rogers and Xiaowei Wang for proof reading. This work is supported in part by grants from the Susan G. Komen Foundation (QY), Siteman Cancer Center Award (QY) and NIH CA129440 (QY).

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Author notes

  1. Y Jia, W Song and F Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, USA

    Y Jia, W Song, F Zhang, J Yan & Q Yang

  2. The colorectal cancer surgery department, The 3rd affiliated hospital of Harbin Medical University, Harbin, China

    Y Jia

  3. Department of Radiology, University of Washington Medical Center, Seattle, WA, USA

    J Yan

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  1. Y Jia
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Correspondence to Q Yang.

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Jia, Y., Song, W., Zhang, F. et al. Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway. Oncogene 32, 1943–1949 (2013). https://doi.org/10.1038/onc.2012.211

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