REV7可以抵消DNA双链断裂切除,并影响PARP抑制
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
概括
REV7的损失恢复了BRCA1缺乏细胞中的同源重组 (HR) DNA修复,导致PARP抑制剂耐药性. 这种REV7功能是53BP1的下游,并影响DNA修复路径的选择.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 癌症研究 癌症研究
背景情况:
- 同源重组 (HR) 对于无错误的DNA双链断裂 (DSB) 修复至关重要.
- 在某些癌症中,BRCA1缺乏导致PARP抑制剂的合成致死性.
- 药物耐药性可能来自HR恢复,但BRCA1-独立HR恢复的机制尚不清楚.
研究的目的:
- 研究BRCA1独立HR恢复的机制.
- 确定参与BRCA1缺陷细胞中DNA修复途径选择的新型因素.
- 了解REV7在DNA修复和PARP抑制剂耐药性的作用.
主要方法:
- 使用了老鼠和人类细胞系.
- 研究了DNA修复途径,包括HR和非同类末端结合 (NHEJ).
- 分析了使用染色质通路对DSB的蛋白质招募.
- 研究了ATM激酶抑制的作用.
主要成果:
- 在BRCA1缺乏细胞中,REV7 (MAD2L2) 的损失重新建立了CTIP依赖的末端切除.
- REV7损失恢复HR,从而赋予PARP抑制剂的耐药性.
- 在DSB中REV7的招募取决于H2AX-MDC1-RNF8-RNF168-53BP1通路.
- 在免疫球蛋白类切换重组过程中,REV7阻断了DSB切除,以促进NHEJ.
- 通过ATM激酶抑制,可以逆转REV7介导的抗性.
结论:
- 在BRCA1缺乏细胞中,REV7在阻断HR和促进NHEJ方面发挥着关键作用.
- 在协调DSB修复路径选择方面,REV7在53BP1的下游作用.
- 针对REV7可能提供克服PARP抑制剂耐药性的策略.
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