The mechanism of tissue specific carcinogenesis by the deficiency of the centrosomal BRCA1 complex

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15233
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tohoku University
• Principal Investigator: Yoshino Yuki 東北大学, 加齢医学研究所, 助教 (60755700)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 中心体 / BRCA1 / 乳がん / RACK1 / PLK1 / Aurora A

Outline of Final Research Achievements

In this study, we found that RACK1 enhances the interaction between Aurora A and PLK1 as a scaffold to promote activation of PLK1. Previously, PLK1 is reported to act the G2 and M phases. We found PLK1 supported by RACK1 contributed to centriole duplication in the S phase. Excess RACK1 overactivated PLK1 resulting in premature disengagement and centriole reduplication in the S phase. Thus, excess RACK1 may contribute to carcinogenesis via inducing chromosomal instability by centrosome aberration.
Next, we determined the precise localizing position of BRCA1 in centrosomes using structured-illumination microscopy. BRCA1 localized at the base of the centrioles, not in the pericentriolar material. In addition, we identified several amino acid residues of which phosphorylation status was different between cytosol and centrosomes. The role of phosphorylation of these residues in the regulation of BRCA1 localization should be investigated in future studies.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

BRCA1は遺伝性乳がん卵巣がん症候群の原因であるが、その組織特異的発がんの分子機構が十分明らかでないため、BRCA1変異キャリアの発がんリスクの正確な評価ができない例がある。本研究でBRCA1複合体による中心体制御機構の一端が明らかになったことは、BRCA1変異が細胞機能に及ぼす影響をより正確な判定に寄与しうる。また、発がん機構が明らかになれば、これに介入し、発がんを抑制する方法の開発につながる可能性があり、新たながん治療法、がん予防法の開発に貢献することができると考えられる。