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DNA损伤通过抑制RNA聚合酶II延伸的抑制来调节替代拼接
Manuel J Muñoz1, M Soledad Pérez Santangelo, Maria P Paronetto
1Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Argentina.
Cell
|May 20, 2009
概括
紫外线照射 (UV) 通过影响RNA聚合酶II来改变DNA损伤反应期间的RNA拼接. 这种独立于p53的机制影响着亡和基因表达.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 生物化学 生物化学
背景情况:
- DNA损伤会触发亡,这个过程通常由替代拼接 (AS) 调节.
- 关联DNA损伤,AS和亡的精确控制机制在很大程度上仍未被阐明.
- 对于RNA聚合酶II酸化在调节DNA损伤期间AS的作用尚不清楚.
研究的目的:
- 研究紫外线 (UV) 辐射对共转录替代拼接 (AS) 的影响.
- 阐明RNA聚合酶II碳氧终端域 (CTD) 酸化在紫外线诱导的AS中的作用.
- 确认紫外线诱导的AS在p53独立的亡中的相关性.
主要方法:
- 在体内和实时估计转录延长.
- 使用RNA聚合酶II的相和非酸化的CTD突变物.
- 采用对拼接敏感的微阵列来分析基因表达和AS变化.
- 评估bcl-x替代拼接逆转对紫外线诱导的亡的影响.
主要成果:
- 紫外线照射抑制了转录延长,并以p53独立的方式改变了共转录AS.
- 对RNA聚合酶IICTD的高酸化被确定为UV诱导AS的关键调解者.
- 模仿酸化的CTD突变体复制紫外线对AS的影响,而非酸化的突变体阻止了它.
- 逆转bcl-x基因中的AS变化可以防止p53缺乏细胞的紫外线诱导的亡.
- 改变AS的基因和在紫外线暴露后减少表达之间存在显著的重叠.
结论:
- 紫外线诱导的DNA损伤通过RNA聚合酶II CTD高酸化和抑制延长来调节共转录AS.
- 这种机制在p53独立的亡中起着至关重要的作用.
- 对AS的转录合是细胞DNA损伤反应的重要特征.
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