RAD51B-RAD51C-RAD51D-XRCC2腫瘍抑制体の構造と機能

Luke A Greenhough¹, Chih-Chao Liang¹, Ondrej Belan^1,2,3

¹The Francis Crick Institute, London, UK.

Nature

|June 21, 2023

まとめ

RAD51B-RAD51C-RAD51D-XRCC2複合体 (BCDX2) は,複製フォークの保護と二重鎖破裂の修復に不可欠なRAD51フィラメントを組み立てることで,がんを予防します.

科学分野:

分子生物学
構造生物学
遺伝学

背景:

ホモログ的再結合はDNA修復,複製フォークの安定性,そして微分化に不可欠である.
BRCA2やRAD51のような再結合遺伝子の変異は,癌やファンコーニ貧血と関連しています.
DNA修復とがん予防におけるRAD51パラログの正確な分子機能は,ほとんど不明である.

研究の目的:

DNA修復とがん予防におけるRAD51パラログ複合体 (BCDX2) の構造的および機能的役割を明らかにする.

主な方法:

クリオ電子顕微鏡
AlphaFold2モデリング
構造プロテオミクス
生化学的測定法
単一分子分析

主要な成果:

RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2) 複合体の構造を決定した.
RAD51C-RAD51D-XRCC2はフィラメント内のRAD51プロトメアを模倣し,RAD51Bはダイナミックである.
BCDX2は,RAD51BとRAD51Cの結合ATPアゼ活動によってRAD51フィラメントの核形成と拡張を刺激する.
BCDX2は,単一鎖DNAのRAD51アセンブリをオーケストラするのに不可欠です.

結論:

BCDX2は,レプリケーションフォークの保護とRAD51フィラメント形成による二重鎖破裂の修復に重要な役割を果たします.
BCDX2複合体は,腫瘍抑制に不可欠なDNA修復経路の重要な媒介者です.

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