Nuclear–cytoplasmic shuttling of bard1 contributes to its proapoptotic activity and is regulated by dimerization with brca1

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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DNA DAMAGE RESPONSE AND DNA REPAIR Article 27 July 2024 P50 MONO-UBIQUITINATION AND INTERACTION WITH BARD1 REGULATES CELL CYCLE PROGRESSION AND MAINTAINS GENOME STABILITY Article Open

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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. AUTHOR INFORMATION Author notes * José Antonio Rodriguez Present address: Department of Medical Oncology, Academic Hospital, Vrije

Universiteit Amsterdam, 1081HV, Amsterdam, The Netherlands * José Antonio Rodriguez and Stefan Schüchner: These two authors contributed equally to this work AUTHORS AND AFFILIATIONS *

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 Authors * José Antonio Rodriguez View author publications You can also search for this author inPubMed Google

Scholar * Stefan Schüchner View author publications You can also search for this author inPubMed Google Scholar * Wendy W Y Au View author publications You can also search for this author

inPubMed Google Scholar * Megan Fabbro View author publications You can also search for this author inPubMed Google Scholar * Beric R Henderson View author publications You can also search

for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Beric R Henderson. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

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 Download citation * Received: 20 August 2003 * Revised: 17 October 2003 * Accepted: 21 October 2003 * Published: 01 December 2003 *

Issue Date: 11 March 2004 * DOI: https://doi.org/10.1038/sj.onc.1207302 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * BARD1 * BRCA1 * nuclear

export * cancer * apoptosis