p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage

Juhong Jiang, Eddy S. Yang, Guochun Jiang, Somaira Nowsheen, Hong Wang, Tong Wang, Yihan Wang, Dean Billheimer, A. Bapsi Chakravarthy, Melissa Brown, Bruce Haffty, Fen Xia

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Subcellular localization regulates BRCA1 function, and BRCA1 is exported to the cytoplasm following DNA damage in a p53-dependent manner. Because more than 50% of solid tumors harbor p53 mutations, it is possible that genetically wild-type (wt) BRCA1 is functionally abnormal through compromised nuclear-cytoplasmic shuttling in sporadic breast cancer patients with dysfunctional p53. In this study, we have investigated the mechanisms of p53-dependent BRCA1 subcellular distribution and DNA damage-induced nuclear export, as well as the impact on the resulting cytotoxic response to therapy in human breast cancer. We first show that p53 mediates BRCA1 nuclear export via protein - protein binding, rather than by modulation of its transcription. Furthermore, it is the C-terminal (BRCT) region of BRCA1 that is critical for its interaction with p53, and p53 may promote BRCA1 nuclear export by interrupting the association of BRCA1 with BARD1. In sporadic breast cancer specimens, dysfunctional p53 strongly correlates with nuclear retention of sequence-verified wt BRCA1. This p53-dependent BRCA1 shuttling determines cellular susceptibility to DNA damage as augmentation of cytosolic BRCA1 significantly enhances cancer cell susceptibility to ionizing radiation. Taken together, our data suggest that p53 dysfunction compromises nuclear export of wt BRCA1 as a mechanism to increase cellular resistance to DNA damage in sporadic breast cancer. We propose that targeting nuclear BRCA1 to the cytoplasm may offer a unique strategy to sensitize p53-deficient sporadic breast cancers to DNA damage - based therapy.

Original languageEnglish (US)
Pages (from-to)5546-5557
Number of pages12
JournalCancer Research
Volume71
Issue number16
DOIs
StatePublished - Aug 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Jiang, J., Yang, E. S., Jiang, G., Nowsheen, S., Wang, H., Wang, T., Wang, Y., Billheimer, D., Chakravarthy, A. B., Brown, M., Haffty, B., & Xia, F. (2011). p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage. Cancer Research, 71(16), 5546-5557. https://doi.org/10.1158/0008-5472.CAN-10-3423