Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity

Oncogene. 2003 May 15;22(19):2926-31. doi: 10.1038/sj.onc.1206522.


Carriers of mutations in the BRCA2 gene are at a highly elevated risk of breast and other cancers. The BRCA2 gene encodes a very large protein thought to play a role in DNA repair. To examine the effect of mutation of BRCA2 on sensitivity to ionizing radiation, we used a previously described mouse model system (Brca2(Tr)) in which the Brca2 open reading frame is truncated. Mouse embryo fibroblasts carrying this mutation have a proliferative defect, which we show here can be substantially rescued by genetic ablation of p53. Proliferating Brca2(Tr/Tr)/p53(-/-) cells, like Brca2(Tr/Tr) cells, show genomic instability. We used the clonogenic survival assay, which depends on the ability of cells to proliferate, to examine the cell cycle dependence of radiation sensitivity of Brca2(Tr/Tr)/p53(-/-) compared to p53(-/-) and wild-type cells. This showed that the Brca2 mutation had little effect on cells irradiated in quiescence but sensitized proliferating cells to ionizing radiation on a p53(-/-) background. These results suggest that the major role of Brca2 in mediating cell survival after irradiation is in the S and G(2) phases of the cell cycle.

MeSH terms

  • Animals
  • Breast Neoplasms / radiotherapy
  • Cell Cycle* / genetics
  • Cell Cycle* / radiation effects
  • Cell Line
  • Centrosome / radiation effects
  • Female
  • Genes, BRCA2*
  • Humans
  • In Vitro Techniques
  • Mice
  • Mutation*
  • Radiation Tolerance / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Tumor Suppressor Protein p53