RHINOは,MMEJにミトーシスのDNAの破損を修復するように指示します

Alessandra Brambati¹, Olivia Sacco¹, Sarina Porcella¹

¹Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Science (New York, N.Y.)

|July 13, 2023

まとめ

マイクロホモロジー媒介の末端結合 (MMEJ) は,RHINOによるミトーシスに限定され,DNA二重鎖破裂修復において決定的な要因である. この発見は,MMEJ

科学分野:

分子生物学
遺伝学
癌研究

背景:

DNAの二重鎖断裂 (DSB) は,主にインターフェーズ中の非同類末端結合 (NHEJ) と同類再結合 (HR) によって修復される.
マイクロホモロジーによる末端結合 (MMEJ) は二次的なDNA修復経路とみなされた.
9-1-1複合体 (RAD9A-RAD1-HUS1) とRHINOはDNA損傷反応に関与しています.

研究の目的:

ミクロホモロジー媒介の末端結合 (MMEJ) DNA修復に関与する新しい要因を特定する.
細胞サイクル中のMMEJを制御する規制メカニズムを明らかにする.
ガンにおけるMMEJ経路の治療的影響を探る.

主な方法:

CRISPR-Cas9ベースの合成致死性スクリーンは癌細胞に用いられました.
タンパク質の局所化と相互作用を研究するために,免疫光と共免疫降水測定法を使用した.
細胞周期の異なる段階におけるMMEJ活動の分析

主要な成果:

9-1-1複合体とRHINOのサブユニットは,MMEJの重要な要因として特定されました.
RHINOはMMEJをミトーシスに制限し,M段階ではPLK1によって蓄積され,リン酸化される.
RHINOは,ポリメラーゼ θ (Polθ) をミトーシス中のDSBに誘導し,持続的なS相誘導のDSBを修復する.

結論:

RHINOは,MMEJの細胞周期依存の調節に重要な役割を果たしています.
ミトーシスのMMEJは残留DSBを修復し,バックアップメカニズムを超えてその重要性を強調します.
発見は,POLQ,BRCA1/2,およびPolθおよびPARP阻害剤の有効性に関する洞察を提供します.

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