A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability (original) (raw)

Oncogene volume 17, pages 3115–3124 (1998)Cite this article

Abstract

Germline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos deficient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These findings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to γ-irradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53−/− background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. **Brca1**−/− fibroblasts are not viable, nor are **Brca1**−/− : p53−/− fibroblasts. However, proliferative foci arise from **Brca1**−/− : p53−/− cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.

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Authors and Affiliations

  1. Laboratory of Biochemistry and Metabolism, National Institute of Diabetes, Digestive and Kidney Diseases, Building 10, 9N105, Bethesda, 20892, Maryland, USA
    Shan-Xiang Shen, Xiaoling Xu, Cuiling Li, Michael Weinstein, Lin Chen & Chu-Xia Deng
  2. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Zoë Weaver & Thomas Ried
  3. Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Xin-Yuan Guan

Authors

  1. Shan-Xiang Shen
  2. Zoë Weaver
  3. Xiaoling Xu
  4. Cuiling Li
  5. Michael Weinstein
  6. Lin Chen
  7. Xin-Yuan Guan
  8. Thomas Ried
  9. Chu-Xia Deng

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Shen, SX., Weaver, Z., Xu, X. et al. A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability.Oncogene 17, 3115–3124 (1998). https://doi.org/10.1038/sj.onc.1202243

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