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Originally published In Press as doi:10.1074/jbc.M200769200 on March 29, 2002

J. Biol. Chem., Vol. 277, Issue 24, 21315-21324, June 14, 2002
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BARD1 Induces BRCA1 Intranuclear Foci Formation by Increasing RING-dependent BRCA1 Nuclear Import and Inhibiting BRCA1 Nuclear Export*

Megan Fabbro, Jose A. RodriguezDagger , Richard Baer§, and Beric R. Henderson

From the Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, 2145, New South Wales, Australia and the § Institute of Cancer Genetics, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032

BRCA1 is a tumor suppressor with several important nuclear functions. BRCA1 has no known cytoplasmic functions. We show here that the two previously identified nuclear localization signals (NLSs) are insufficient for nuclear localization of BRCA1 due to the opposing action of an NH2-terminal nuclear export signal. In transfected breast cancer cells, BRCA1 nuclear localization requires both the NLSs and NH2-terminal RING domain region; mutating either of these sequences shifts BRCA1 to the cytoplasm. The BRCA1 RING element mediates nuclear import via association with BARD1, and this is not affected by cancer-associated RING mutations. Moreover, BARD1 directly masks the BRCA1 nuclear export signal, and the resulting block to nuclear export is requisite for efficient import and nuclear localization of ectopic and endogenous BRCA1. Our results explain why BRCA1 exon 11 splice variants, which lack the NLSs but retain the RING domain, are frequently detected in the nucleus and in nuclear foci in vivo. In fact, co-expression of BARD1 promoted formation of DNA damage-induced nuclear foci comprising ectopic wild-type or NLS-deficient BRCA1, implicating BARD1 in nuclear targeting of BRCA1 for DNA repair. Our identification of BARD1 as a BRCA1 nuclear chaperone has regulatory implications for its reported effects on BRCA1 protein stability, ubiquitin ligase activity, and DNA repair.

* This work was supported by grants from the National Health and Medical Research Council of Australia and the Leo & Jenny Cancer Foundation (to B. R. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Dept. of Medical Oncology, Academic Hospital Vrije Universiteit Amsterdam, 1081HV, Amsterdam, The Netherlands.

To whom correspondence should be addressed: Westmead Institute for Cancer Research, Westmead Millennium Institute, Darcy Road (P. O. Box 412), Westmead, New South Wales 2145, Australia. Tel.: 61-2-9845-9057; Fax: 61-2-9845-9102; E-mail: beric_henderson@wmi.usyd.edu.au.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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