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J. Biol. Chem., Vol. 279, Issue 27, 28574-28584, July 2, 2004

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DNA Damage Induces p53-dependent BRCA1 Nuclear Export^*

Zhihui Feng, Lisa Kachnic, Junran Zhang, Simon N. Powell, and Fen Xia

From the Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

The tumor suppressor gene BRCA1 plays an important role in the response to DNA damage. BRCA1 function is regulated by a variety of mechanisms including transcriptional control, phosphorylation, and protein-protein interactions. Recent studies have shown that BRCA1 is a nuclear-cytoplasmic shuttle protein. Its subcellular localization is controlled by a nuclear localization signal-mediated nuclear import via the importin receptor pathway and a nuclear export signal-facilitated nuclear export through a CRM1-dependent pathway. Using the human breast cancer cell line, MCF7, the subcellular distribution of BRCA1 was assessed by immunohistochemical staining and Western blotting analyses of fractionated subcellullar extracts. Ionizing radiation stimulated BRCA1 nuclear export in a dose-dependent manner. This DNA damage-induced BRCA1 nuclear export utilized a CRM1-dependent mechanism and also required wild-type p53, whose function was abrogated by the E6 protein in MCF7 cells. In addition, the dependence on p53 was confirmed using a second cell type operating a tetracycline-inducible system. The effect of ionizing radiation on BRCA1 export was observed in every phase of the cell cycle, although BRCA1 localization did vary between the G₁, S, and G₂/M phases. These results imply that, in addition to ATM-, ATR-, and Chk2-dependent phosphorylations, cytoplasmic relocalization of BRCA1 protein is a mechanism whereby BRCA1 function is regulated in response to DNA damage.

Received for publication, April 14, 2004

^* This work was supported in part by a Breast Cancer Research Grant from the Massachusetts Department of Public Health, an Avon Breast Cancer Research Grant, and a Grant from Susan G. Komen Breast Cancer Foundation (to F. X.) as well as a Dana-Farber/Partners Cancer Care Grant and the Harvard Breast Cancer SPORE (to S. N. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Radiation Oncology, Vanderbilt University School of Medicine, 1301 22nd Ave., Nashville, TN 37232. Tel.: 615-322-2555; Fax: 615-343-6589; E-mail: fen.xia{at}vanderbilt.edu.

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