CtIP-BRCA1は,細胞サイクル全体でDNAの二重鎖破裂修復経路の選択を調節する
1Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Nature
|April 10, 2009
まとめ
CtIPタンパク質は細胞サイクルスイッチとして作用し,DNAの二重鎖の断裂修復を指揮する. セリン327におけるそのリン酸化はS/G2におけるエラーフリーな同類再結合を促進し,MMEJはG1において優位である.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- 遺伝学 遺伝学とは
背景:
- DNAの二重鎖断裂 (DSBs) は,細胞サイクル全体で異なる経路で修復されます.
- 非同類末端結合 (NHEJ) とマイクロホモロジー媒介末端結合 (MMEJ) は,G1で流行するエラーが多い経路です.
- ホモロゴス再結合 (HR) は,S/G2フェーズで好まれるエラーフリー経路である.
研究 の 目的:
- DSBにおける異なるDNA修復経路の選択を制御するメカニズムを解明する.
- 細胞サイクル中のDSB修復経路選択を指示するCtIP (RBBP8) の役割を特定する.
主な方法:
- 鳥類のB細胞系DT40を使用した.
- DSB修復経路におけるCtIPの機能を調査しました.
- CtIPセリン327のリン酸化とBRCA1のリクルートメントが修復フィデリティに与える影響を分析した.
主要な成果:
- CtIPは,G1のMMEJとS/G2のHRの両方にとって不可欠です.
- CtIPのHR機能は,MMEJではないが,セリン327のリン酸化とBRCA1募集に依存している.
- シリアン327のリン酸化が欠けている変異CtIPはHRを損なっており,損傷後に単一鎖DNAを減少させ,MMEJは影響を受けない.
結論:
- セリン327でのCtIPのリン酸化は,細胞周期に依存する分子スイッチとして作用する.
- このスイッチは,BRCA1募集とともに,DSBの修復を誤りやすいエンド・ジョインから,誤りのない同型再結合にシフトさせます.
- CtIPは,DSB修復経路の選択を規制することによって,ゲノムの完全性を維持する上で重要な役割を果たします.
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