在与复制分叉碰撞时,RNAPII依赖的ATM信号
Elias Einig1, Chao Jin1, Valentina Andrioletti1,2
1Department of Medical Oncology and Pulmonology, University Hospital Tübingen, Otfried-Mueller-Str 14, 72076, Tübingen, Germany.
Nature communications
|August 24, 2023
概括
瘤信号导致转录复制冲突 (TRCs),导致DNA损伤. 这项研究表明,TRCs激活ATM激酶用于DNA修复,而WRNIP1调节了这一过程.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 细胞生物学 细胞生物学
背景情况:
- 通过致癌信号的RNA聚合酶II (RNAPII) 的放松调节会导致转录复制冲突 (TRCs).
- TRCs可以导致癌细胞的DNA损伤和基因组不稳定.
- 激酶激活对于DNA修复途径至关重要.
研究的目的:
- 调查RNAPII在TRCs中核ATM激酶激活中的作用.
- 阐明WRNIP1和HUWE1在TRC期间调节ATM激活中的功能.
- 了解细胞对复制性压力的反应.
主要方法:
- 使用细胞和分子生物学技术研究了TRC中的RNAPII行为和ATM激酶激活.
- 利用HUWE1中的基因突变研究其对WRNIP1结合和ATM激活的影响.
- 采用基尿素处理来诱导TRC并评估WRNIP1转位和ATM激活.
主要成果:
- 延长RNAPII核细胞在TRC中激活ATM激酶以促进DNA修复.
- ATPase WRNIP1 与RNAPII结合并限制了ATM的激活.
- 为了使WRNIP1与RNAPII结合,需要HUWE1的全方位酶活性;它的突变破坏了这种相互作用,导致ATM激活的增加.
- TRCs和WRNIP1转位被基尿素迅速诱导,激活ATM进行DNA修复.
结论:
- TRCs作为ATM激酶激活的平台,促进DNA修复.
- WRNIP1作为TRC的ATM激活的负调节器,需要HUWE1活动.
- TRCs和WRNIP1转位代表了一个可控的机制,用于停止复制分叉并激活ATM以应对复制应激.
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