title: p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage.
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.
authors: Departments of Radiation Oncology and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.
authors: Juhong
authors: J
authors: Jiang
authors: Eddy S
authors: ES
authors: Yang
authors: Guochun
authors: G
authors: Jiang
authors: Somaira
authors: S
authors: Nowsheen
authors: Hong
authors: H
authors: Wang
authors: Tong
authors: T
authors: Wang
authors: Yihan
authors: Y
authors: Wang
authors: Dean
authors: D
authors: Billheimer
authors: A Bapsi
authors: AB
authors: Chakravarthy
authors: Melissa
authors: M
authors: Brown
authors: Bruce
authors: B
authors: Haffty
authors: Fen
authors: F
authors: Xia
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D009154:Mutation; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53