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

Jiang, Juhong, Yang, Eddy S., Jiang, Guochun, Nowsheen, Somaira, Wang, Hong, Wang, Tong, Wang, Yihan, Billheimer, Dean, Chakravarthy, A. Bapsi, Brown, Melissa, Haffty, Bruce and Xia, Fen (2011) p53-Dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage. Cancer Research, 71 16: 5546-5557. doi:10.1158/0008-5472.CAN-10-3423


Author Jiang, Juhong
Yang, Eddy S.
Jiang, Guochun
Nowsheen, Somaira
Wang, Hong
Wang, Tong
Wang, Yihan
Billheimer, Dean
Chakravarthy, A. Bapsi
Brown, Melissa
Haffty, Bruce
Xia, Fen
Title p53-Dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2011-08-01
Year available 2011
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-10-3423
Open Access Status Not yet assessed
Volume 71
Issue 16
Start page 5546
End page 5557
Total pages 12
Place of publication Philadelphia, United States
Publisher American Association for Cancer Research
Language eng
Subject 2730 Oncology
1306 Cancer Research
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.
Keyword Tumor-suppressor gene
Repair function
Breast-cancer
P53
Mutations
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 CA118158-02
UL1 RR024975
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 30 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 33 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sun, 04 Sep 2011, 11:12:26 EST by System User on behalf of School of Chemistry & Molecular Biosciences