The Function of BARD1 in Centrosome Regulation in Cooperation with BRCA1/OLA1/RACK1.

Kei Otsuka,Yuki Yoshino,Huicheng Qi,Natsuko Chiba

doi:10.3390/genes11080842

Abstract

Breast cancer gene 1 (BRCA1)-associated RING domain protein 1 (BARD1) forms a heterodimer with BRCA1, a tumor suppressor associated with hereditary breast and ovarian cancer. BRCA1/BARD1 functions in multiple cellular processes including DNA repair and centrosome regulation. Centrosomes are the major microtubule-organizing centers in animal cells and are critical for the formation of a bipolar mitotic spindle. BRCA1 and BARD1 localize to the centrosome during the cell cycle, and the BRCA1/BARD1 dimer ubiquitinates centrosomal proteins to regulate centrosome function. We identified Obg-like ATPase 1 (OLA1) and receptor for activated C kinase (RACK1) as BRCA1/BARD1-interating proteins that bind to BARD1 and BRCA1 and localize the centrosomes during the cell cycle. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 failed to interact, and aberrant expression of these proteins caused centrosome amplification due to centriole overduplication only in mammary tissue-derived cells. In S-G2 phase, the number of centrioles was higher in mammary tissue-derived cells than in cells from other tissues, suggesting their involvement in tissue-specific carcinogenesis by BRCA1 and BARD1 germline mutations. We described the function of BARD1 in centrosome regulation in cooperation with BRCA1/OLA1/RACK1, as well as the effect of their dysfunction on carcinogenesis.

Highlights

Germline mutations in Breast Cancer gene 1 (BRCA1) are associated with familial breast and ovarian cancers [1]
We described the function of BRCA1-associated RING domain 1 (BARD1) in centrosome regulation together with Breast cancer gene 1 (BRCA1)
Germline mutations of BARD1 are present in hereditary breast and ovarian cancers [69,91,92,93,94]

Summary

Introduction

Germline mutations in Breast Cancer gene 1 (BRCA1) are associated with familial breast and ovarian cancers [1]. Centrosome duplication is initiated by the physical separation of a pair of centrioles (centriole disengagement) in late mitosis-early G1 phase. The PCM contains γ-tubulin ring complexes (γ-TuRCs) that play important roles in nucleating, anchoring, and positioning MTs. The single centrosome in the G1 phase duplicates only once per cell cycle (in S phase), and one centrosome is inherited by each daughter cell [8]. The new daughter centriole starts to form a procentriole perpendicular to each mother centriole in early S phase. The mother and daughter centrioles are disengaged in late which play roles inCentrosome nucleating, anchoring, and positioning microtubules (MTs). We describe the tissuespecific centrosomes per cell.effects of dysregulation of these processes on carcinogenesis in breast cancer

Centrosome Aberrations in Cancer

OLA1 and RACK1 Function in the Regulation of Centrosome Number Together with

BARD1 Isoforms and Cancer

Findings

Summary and Perspective