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 BARD1beta. 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 BARD1beta coimmunoprecipitates with Aurora B and BRCA2. We used selective small interfering RNAs to distinguish the functions of FL BARD1 and BARD1beta. 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 BARD1beta 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 BARD1beta 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 BARD1beta.
Highlights
Breast and ovarian cancers with mutations in BRCA1 and BRCA2 show a severe genomic instability phenotype [1]
Double labeling with anti-BRCA1-associated ring domain protein 1 (BARD1) and anti–h-tubulin antibodies revealed that BARD1 staining was partially localized along mitotic spindle microtubules in metaphase and early anaphase cells (Fig. 1A)
We show novel BARD1 functions during the late phases of mitosis, which involve interactions with transforming acidic coiled coil– containing protein 1 (TACC1), Aurora B, and BRCA2
Summary
Breast and ovarian cancers with mutations in BRCA1 and BRCA2 show a severe genomic instability phenotype [1]. Genomic instability and a premalignant phenotype are features of BRCA1-associated ring domain protein 1 (BARD1)–deficient cells [2], causing early embryonic death of BARD1 knockout mice [3]. BARD1 and BRCA1 form a stable heterodimer via their respective. NH2 terminal RING finger domains [4], and either Bard or Brca deletion induces breast cancer in tissue-specific conditional knockout mice [5]. BARD1 is the major protein-binding partner of BRCA1, with whom it forms a stable heterodimer and acts in tumor suppressor functions but has BRCA1-independent functions in apoptosis [6, 7]. The BARD1-BRCA1 heterodimer is an E3 ubiquitin ligase implicated in DNA repair and homologous recombination [8, 9], centrosome duplication [10], and mitotic spindle assembly [11], which are essential functions for maintaining genomic stability [10, 12]
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