Genome-wide analysis of factors affecting transcription elongation and DNA repair: a new role for PAF and Ccr4-not in transcription-coupled repair.
Genome-wide analysis of factors affecting transcription elongation and DNA repair: a new role for PAF and Ccr4-not in transcription-coupled repair.
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DOI：
10.1371/journal.pgen.1000364
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Aguilera A
中科院分区：
文献类型：
--
作者：
Gaillard H;Tous C;Botet J;González-Aguilera C;Quintero MJ;Viladevall L;García-Rubio ML;Rodríguez-Gil A;Marín A;Ariño J;Revuelta JL;Chávez S;Aguilera A
RNA聚合酶在转录延伸期间经常处理许多障碍物，这些障碍物需要被移除以恢复转录。一种重要类型的障碍由DNA损伤组成，其通过转录偶联修复（TC-NER）（核苷酸切除修复的特定子途径）去除。为了提高我们对转录延伸及其与TC-NER偶联的认识，我们使用非必需敲除突变的酵母文库来筛选赋予对转录延伸抑制剂麦考酚酸和DNA损伤剂4-硝基喹啉-N-氧化物的抗性的基因。我们的数据提供的证据表明，SAGA和Ccr4-Not复合物，介体，Bre1，Bur2和Fun12的亚基影响转录延伸到不同程度。鉴于TC-NER对RNA聚合酶II转录的依赖性以及已知参与TC-NER的少数蛋白质与转录相关的事实，我们对选择的突变体进行了深入的TC-NER分析。我们发现PAF和Ccr4-Not复合物的突变体在TC-NER中受损。这项研究提供的证据表明，PAF和Ccr4-Not是必需的有效的TC-NER在酵母中，解开这些转录复合物的一个新的功能，并打开新的视角，了解TC-NER及其功能的相互联系与转录延伸。处理DNA损伤是原核和真核细胞最重要的任务之一。这与基因内部发生的损伤特别相关，在活跃转录的DNA链中，因为转录不能通过受损位点进行，持续的损伤可能导致基因组不稳定或细胞死亡。细胞已经进化出特定的机制来修复这些DNA损伤，其功能障碍导致人类严重的遗传综合征。尽管经过多年的深入研究，转录偶联修复的机制仍然知之甚少。为了深入了解这种现象，我们在真核生物酿酒酵母中进行了全基因组筛选，以寻找影响这种与转录相关的修复的基因。我们的研究使我们能够识别和证明具有先前已知转录功能的因子在DNA修复中的新作用，为理解DNA修复及其与转录的功能相互联系开辟了新的视角。
RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide. Our data provide evidence that subunits of the SAGA and Ccr4-Not complexes, Mediator, Bre1, Bur2, and Fun12 affect transcription elongation to different extents. Given the dependency of TC-NER on RNA Polymerase II transcription and the fact that the few proteins known to be involved in TC-NER are related to transcription, we performed an in-depth TC-NER analysis of a selection of mutants. We found that mutants of the PAF and Ccr4-Not complexes are impaired in TC-NER. This study provides evidence that PAF and Ccr4-Not are required for efficient TC-NER in yeast, unraveling a novel function for these transcription complexes and opening new perspectives for the understanding of TC-NER and its functional interconnection with transcription elongation. Dealing with DNA lesions is one of the most important tasks of both prokaryotic and eukaryotic cells. This is particularly relevant for damage occurring inside genes, in the DNA strands that are actively transcribed, because transcription cannot proceed through a damaged site and the persisting lesion can cause either genome instability or cell death. Cells have evolved specific mechanisms to repair these DNA lesions, the malfunction of which leads to severe genetic syndromes in humans. Despite many years of intensive research, the mechanisms underlying transcription-coupled repair is still poorly understood. To gain insight into this phenomenon, we undertook a genome-wide screening in the model eukaryotic organism Saccharomyces cerevisiae for genes that affect this type of repair that is coupled to transcription. Our study has permitted us to identify and demonstrate new roles in DNA repair for factors with a previously known function in transcription, opening new perspectives for the understanding of DNA repair and its functional interconnection with transcription.
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