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J. Biol. Chem., Vol. 280, Issue 8, 6993-7001, February 25, 2005

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The BRCA1 RING and BRCT Domains Cooperate in Targeting BRCA1 to Ionizing Radiation-induced Nuclear Foci^*

Wendy W. Y. Au and Beric R. Henderson, National Health and Medical Research Council of Australia Senior Research Fellow

From the Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, New South Wales 2145, Australia

BRCA1 accumulates in nuclear foci during S-phase and reassembles into DNA repair-associated foci after DNA damage, reflecting its role in genome maintenance. BRCA1 comprises a RING domain at the N terminus and a BRCT domain at the C terminus, through which it associates with DNA repair proteins. The key sequences that target BRCA1 to DNA damage-induced foci have not been identified. Here, we mapped the BRCA1 foci-targeting domains of yellow fluorescence protein (YFP)-tagged BRCA1 in MCF-7 breast cancer cells exposed to ionizing radiation (IR). Cancer mutations specific to the BRCT domain, but not the RING domain, abolished BRCA1 recruitment to IR-induced foci. The YFP-BRCT domain itself, however, localized poorly at IR-induced foci, and the RING domain and other sequences were negative. We discovered that only when the RING and BRCT domains were combined was foci targeting restored to levels observed for wild-type BRCA1. The RING-BRCT fusion co-localized at foci with the MDC1 DNA damage response factor and inhibited entry of endogenous BRCA1 into nuclear foci. Our results explain why exon 11-deficient BRCA1 splice variants are targeted to IR-induced foci even though they are incapable of repairing DNA damage. We propose that both RING and BRCT domains together target BRCA1 to large focal assemblies at DNA double-stranded breaks.

Received for publication, August 4, 2004 , and in revised form, November 15, 2004.

^* This work was supported by the National Health and Medical Research Council of Australia. 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.

Recipient of a National Health and Medical Research Council of Australia Dora Lush postgraduate scholarship.

To whom correspondence should be addressed: Westmead Millennium Inst., Darcy Rd., P. O. Box 412, Westmead, NSW 2145, Australia. Tel.: 61-2-9845-9057; Fax: 61-2-9845-9102; E-mail: beric_henderson{at}wmi.usyd.edu.au.

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