Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination
Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination
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DOI：
10.1016/j.molcel.2003.08.010
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发表时间：
2003-09-01
期刊：
影响因子：
16
通讯作者：
Aguilera, A
中科院分区：
文献类型：
--
作者：
Huertas, P;Aguilera, A
遗传不稳定性，一种与发育调节过程、癌症和遗传性疾病相关的现象，可以由转录诱导。然而，转录相关的遗传不稳定性的机制还不清楚。分析S. THO/TREX是一种在转录和mRNA代谢的界面起作用的保守真核蛋白复合物，酿酒酵母突变体提供了转录延伸损伤可引起过度重组的证据。在这里，我们表明，使用hpr 1Delta突变体，新生的mRNA可以降低转录延伸效率，促进重组。如果在转录过程中，新生mRNA被锤头状核酶自切割，则hpr 1Delta细胞的转录缺陷和过度重组表型被抑制。废除过度重组的RNA酶H1和DNA的分子检测：RNA杂交表明，这些cotranscriptionally在hpr 1Delta细胞中形成。这些数据支持一个模型来解释重组，转录和mRNA代谢之间的联系，并提供了一个新的视角来理解转录相关的重组。
Genetic instability, a phenomenon relevant for developmentally regulated processes, cancer, and inherited disorders, can be induced by transcription. However, the mechanisms of transcription-associated genetic instability are not yet understood. Analysis of S. cerevisiae mutants of THO/TREX, a conserved eukaryotic protein complex functioning at the interface of transcription and mRNA metabolism, has provided evidence that transcription elongation impairment can cause hyperrecombination. Here we show, using hpr1Delta mutants, that the nascent mRNA can diminish transcription elongation efficiency and promote recombination. If during transcription the nascent mRNA is self-cleaved by a hammerhead ribozyme, the transcription-defect and hyperrecombination phenotypes of hpr1Delta cells are suppressed. Abolishment of hyperrecombination by overexpression of RNase H1 and molecular detection of DNA:RNA hybrids indicate that these are formed cotranscriptionally in hpr1Delta cells. These data support a model to explain the connection between recombination, transcription, and mRNA metabolism and provide a new perspective to understanding transcription-associated recombination.