CDK12控制受损基因的转录,并防止MYC诱导的转录复制冲突
Laura Curti1, Sara Rohban1, Nicola Bianchi1
1Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139, Milan, Italy.
Nature communications
|August 18, 2024
概括
CDK12通过抑制受损基因的转录来防止危险的DNA损伤和转录复制冲突 (TRCs). 失去CDK12会恶化TRC,促进癌症的进化,并提供治疗点.
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:
- 复制性压力对于理解癌症演变和确定治疗点至关重要.
- MYC瘤基因放松调节可能导致转录复制冲突 (TRCs).
研究的目的:
- 研究CDK12在预防TRC和复制性压力的作用.
- 了解CDK12如何调节受损基因的转录.
主要方法:
- 研究了CDK12通过PARP依赖的DNA损伤反应 (DDR) 信号传递和延长竞争性RNA聚合酶II (RNAPII) 对受损基因的招募.
- 评估了CDK12损失或抑制对转录和DNA断裂的影响.
- 在具有或没有CDK12功能的MYC过度表达细胞中检查了TRC.
主要成果:
- CDK12抑制受损基因的转录,防止细胞毒性复制性压力.
- 丢失或抑制CDK12导致受损基因的DDR抗性转录.
- CDK12缺乏会加剧MYC过度表达细胞中的TRCs,导致双链DNA断裂 (DSBs) 并促进基因组不稳定性.
结论:
- CDK12通过抑制受损基因的转录来保护基因组完整性,这对于在瘤基因诱导的TRC中解决DSB至关重要.
- 缺乏CDK12有助于通过串联重复的瘤进化.
- 向CDK12可能会加剧瘤中的复制性压力,这可能是一个潜在的治疗策略.
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