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Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Oncogene volume 23, pages 1809–1820 (2004)Cite this article

Abstract

The breast cancer-associated protein, BARD1, colocalizes with BRCA1 in nuclear foci in the S phase and after DNA damage, and the two proteins form a stable heterodimer implicated in DNA repair, protein ubiquitination, and control of mRNA processing. BARD1 has a BRCA1-independent proapoptotic activity; however, little is known about its regulation. Here, we show that BARD1 localization and apoptotic activity are regulated by nuclear–cytoplasmic shuttling. We identified a functional CRM1-dependent nuclear export sequence (NES) near the N-terminal RING domain of BARD1. The NES forms part of the BRCA1 dimerization domain, and coexpression of BRCA1 resulted in masking of the NES and nuclear retention of BARD1. In transient expression assays, BARD1 apoptotic activity was stimulated by nuclear export, and both apoptotic function and nuclear export were markedly reduced by BRCA1. Similar findings were obtained for endogenous BARD1. Silencing BRCA1 expression by siRNA, or disrupting the endogenous BARD1/BRCA1 interaction by peptide competition caused a reduction in BARD1 nuclear localization and foci formation, and increased the level of cytoplasmic BARD1 correlating with increased apoptosis. Our findings suggest that BRCA1/BARD1 heterodimer formation is important for optimal nuclear targeting of BARD1 and its role in DNA repair and cell survival.

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Acknowledgements

We thank J Holt and R Baer for supplying cDNAs and antibodies. We are grateful to R Kefford and T Cunningham for support at the Westmead Millennium Institute. This work was partly supported by a grant from the National Health and Medical Research Council (NHMRC) of Australia. BRH was supported by an NHMRC Senior Research Fellowship. SS was supported by an Erwin Schroedinger post-doctoral fellowship from the FWF of Austria.

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  1. José Antonio Rodriguez

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

  2. José Antonio Rodriguez and Stefan Schüchner: These two authors contributed equally to this work

Authors and Affiliations

  1. Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, PO Box 412, Darcy Road, Westmead, 2145, NSW, Australia

    José Antonio Rodriguez, Stefan Schüchner, Wendy W Y Au, Megan Fabbro & Beric R Henderson

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Correspondence to Beric R Henderson.

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Rodriguez, J., Schüchner, S., Au, W. et al. Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1. Oncogene 23, 1809–1820 (2004). https://doi.org/10.1038/sj.onc.1207302

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