低氧诱导的转录应激是由ROS诱导的R环介导的
Tiffany S Ma1, Katja R Worth1, Conor Maher1
1Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Nucleic acids research
|October 16, 2023
概括
瘤中缺氧会通过活性氧物种引起R环积累,抑制核糖体RNA合成,并导致癌症的进展. 恢复R循环水平可以挽救这种效应.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 细胞应激反应的应激反应
背景情况:
- 缺氧在固体瘤中普遍存在,与预后不佳,治疗耐药性和转移相关.
- 生理缺氧 (<0.1% O2) 引发复制压力,DNA损伤反应和未折叠的蛋白质反应.
- 缺氧诱导R环的强积累,这是DNA-RNA杂交的结构.
研究的目的:
- 阐明缺氧诱导的R循环积累的机制和后果.
- 为了研究反应性氧物种 (ROS) 在低氧条件下的R循环形成中的作用.
- 了解R-循环如何对低氧瘤的转录应激反应有所贡献.
主要方法:
- 在低氧条件下研究R环积累.
- 评估了非DNA破坏性反应性氧物种 (ROS) 在R循环形成中的作用.
- 监控核糖体RNA (rRNA) 合成和核转位.
- 分析了rDNA上的异染色素标记H3K9me2沉积.
- 耗尽的R环观察救援效应.
主要成果:
- 缺氧诱导的R循环积累取决于ROS.
- 缺氧诱导的R环抑制rRNA合成,并导致核转位.
- 在rDNA上积聚R环,促进H3K9me2沉积,抑制Pol I转录.
- 在低氧中,R-循环耗尽可以挽救rRNA转录和核转位.
结论:
- 一个新的ROS-R-loop-H3K9me2轴调解低氧诱导的转录应激.
- 缺氧诱导的R环通过转录失调显著促进瘤发生.
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