Distinct Roles of BARD1 Isoforms in Mitosis: Full-Length BARD1 Mediates Aurora B Degradation, Cancer-Associated BARD1 Scaffolds Aurora B and BRCA2

¹Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics and ²Department of Medical Genetics and Laboratory Medicine, University Hospitals Geneva, Geneva, Switzerland; ³Laboratoire d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, UMR891 Inserm-Institut Paoli-Calmettes, Marseille, France; and ⁴Laboratory of Genetics, Foundation of Biomedical Research, Academy of Athens, Athens, Greece

^* To whom correspondence should be addressed. E-mail: irmgard.irminger{at}unige.ch.

	Abstract

The BRCA1-associated ring domain protein 1 (BARD1) interacts with BRCA1 via its RING finger domain. The BARD1-BRCA1 complex participates in DNA repair, cell cycle control, genomic stability, and mitotic spindle formation through its E3 ubiquitin ligase activity. Cancer cells express several BARD1 protein isoforms, including the RING finger–deficient variant BARD1. Here, we show that BARD1 has BRCA1-dependent and BRCA1-independent functions in mitosis. BARD1, but not BRCA1, localizes to the midbody at telophase and cytokinesis, where it colocalizes with Aurora B. The 97-kDa full-length (FL) BARD1 coimmunoprecipates with BRCA1, but the 82-kDa BARD1 coimmunoprecipitates with Aurora B and BRCA2. We used selective small interfering RNAs to distinguish the functions of FL BARD1 and BARD1. Depletion of FL BARD1 had only minor effects on cell growth and did not abolish midbody localization of BARD1 staining, but resulted in massive up-regulation of Aurora B. In contrast, suppression of FL BARD1 and BARD1 led to growth arrest and correlated with various mitotic defects and disappearance of midbody localization of BARD1 staining. Our data suggest a novel function of FL BARD1 in Aurora B ubiquitination and degradation, opposing a proproliferative function of BARD1 in scaffolding Aurora B and BRCA2. Thus, loss of FL BARD1 and up-regulation of Aurora B, as observed in cancer cells, can be explained by an imbalance of FL BARD1 and BARD1. [Cancer Res 2009;69(3):1125–34]

Key Words: BRCA1, BRCA2, BARD1, Aurora B, TACC1, mitosis, cytokinesis

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