REV7はDNA二重鎖断裂解剖を逆行させ,PARP抑制に影響する
Guotai Xu1, J Ross Chapman2, Inger Brandsma3
1Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Nature
|March 25, 2015
まとめ
REV7の喪失は,BRCA1欠乏細胞における同類再結合 (HR) DNA修復を回復し,PARP阻害剤耐性につながる. このREV7機能は53BP1のダウンストリームであり,DNA修復経路の選択に影響を与えます.
科学分野:
- 分子生物学は分子生物学である.
- 遺伝学 遺伝学とは
- がん研究 がん研究
背景:
- 同性複合 (HR) は,誤りのないDNA二重鎖断裂 (DSB) 修復に不可欠です.
- BRCA1欠乏症は,特定のがんにおいてPARP阻害剤による合成致死性につながる.
- 薬剤耐性はHR回復から生じることがありますが,BRCA1から独立したHR回復のメカニズムは不明です.
研究 の 目的:
- BRCA1から独立したHR回復のメカニズムを調査する.
- BRCA1欠乏細胞におけるDNA修復経路選択に関与する新しい要因を特定する.
- DNA修復とPARP阻害剤耐性におけるREV7の役割を理解する.
主な方法:
- マウスとヒトの細胞系を利用した.
- HRおよび非同類末端結合 (NHEJ) を含むDNA修復経路の調査.
- クロマチン経路を用いて,DSBへのタンパク質の徴募を分析した.
- ATMキナーゼ抑制の効果を調べました.
主要な成果:
- REV7 (MAD2L2) の喪失は,BRCA1欠乏細胞におけるCTIP依存の末端解剖を再確立する.
- REV7の損失はHRを回復し,PARP阻害剤に対する耐性を授与します.
- REV7のDSBへの採用は,H2AX-MDC1-RNF8-RNF168-53BP1経路に依存しています.
- REV7は,免疫グロブリンクラスのスイッチ再結合中にNHEJを促進するために,DSB解剖をブロックします.
- ATMキナーゼ阻害は,REV7媒介による抵抗を逆転させます.
結論:
- REV7は,BRCA1欠乏細胞におけるHRを阻害し,NHEJを促進する上で重要な役割を果たします.
- REV7は,DSBの修復経路の選択を調整するために,53BP1より下流に作用します.
- REV7をターゲットにすることで,PARP阻害剤に対する耐性を克服する戦略を提供することができる.
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