在复制应激反应中,ADAR1将R环平衡与ATR激活联系在一起
Biao Zhang1,2, Yi Li1, Jieyou Zhang1
1State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300070, China.
Nucleic acids research
|October 13, 2023
概括
编辑RNA的酶ADAR1激活ATR激酶以解决全基因组的RNA-DNA混合体 (R-循环),防止在复制压力期间的DNA损伤. 这个过程涉及ADAR1招募其他蛋白质来解开R循环并增强ATR信号传递.
科学领域:
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
- 生物化学 生物化学
背景情况:
- 不规划的RNA-DNA杂交 (R-循环) 会导致复制压力和DNA损伤.
- 已知ATR激酶可以抑制R循环诱导的复制缺陷.
- R环在激活ATR激酶中的作用尚不清楚.
研究的目的:
- 调查R环是否积极参与ATR激酶激活.
- 阐明R环可能影响ATR激活的机制.
- 了解ADAR1在R循环分辨率和基因组稳定性中的作用.
主要方法:
- 研究了ADAR1,TOPBP1和9-1-1复合体之间的相互作用.
- 利用技术观察蛋白质转位和复制分叉中的复杂组合.
- 评估了ADAR1双链RNA结合域在ATR激活和R循环解析中的作用.
- 研究了ADAR1.1对RNA基酶DHX9和DDX21的招募.
主要成果:
- 核ADAR1促进ATR激活,并解决全基因组的R循环.
- 通过增强TOBP1-RAD9关联,ADAR1有助于TOBP1加载到复制叉上.
- DNA-RNA杂交物诱导ADAR1转移到R循环区域,在那里它招募DHX9和DDX21来解开R循环.
- 这种解使TOPB1能够有效地刺激ATR激酶.
结论:
- ADAR1在R循环清除和ATR激活之间起着至关重要的作用.
- ADAR1核复合体的组合在时间和空间上受到调节,以保持基因组完整性.
- R环与阻塞的复制分叉交叉,调节ADAR1活动以微调ATR信号并保护基因组.
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