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科学家揭示转录偶联DNA修复在细菌中的关键作用及机制
2022-04-04 12:19
来源：小柯机器人

美国纽约大学Evgeny Nudler、中国科学院分子植物科学卓越中心Yu Zhang等研究人员合作揭示转录偶联DNA修复在细菌中的关键作用及机制。这一研究成果于2022年3月30日在线发表在国际学术期刊《自然》上。

研究人员表示，转录耦合DNA修复（TCR）被认为是细菌中核苷酸切除修复（NER）的一个次要亚途径。全局基因组修复被认为是独立于转录进行大部分的修复。TCR也被认为是完全由Mfd——一种边缘NER表型的DNA易位酶介导的。
 
研究人员将细胞交联质谱法与结构、生化和遗传方法结合起来，绘制了TCR复合物（TCRC）内的相互作用，并确定了导致体内NER的实际事件序列。结果表明，RNA聚合酶（RNAP）是DNA损伤的主要传感器，并作为招募NER酶的一个平台。UvrA和UvrD不断地与RNAP联系，形成了一个监视pre-TCRC。在应对DNA损伤时，pre-TCRC招募第二个UvrD单体，形成一个具有螺旋酶能力的UvrD二聚体，促进TCRC的回溯。UvrD-RNAP相互作用的减弱使细胞对基因毒性压力敏感。然后TCRC招募第二个UvrA分子和UvrB来启动修复过程。
 
与传统观点相反，研究人员表明TCR占了染色体修复事件的绝大部分；也就是说，TCR彻底主导了全局基因组修复。结果还表明，TCR在很大程度上与Mfd无关。研究人员提出，Mfd在这一过程中具有间接的作用：它参与清除TCRC前面的障碍性RNAP，也参与修复完成后恢复TCRC的逆行。
 
附：英文原文
 
Title: Crucial role and mechanism of transcription-coupled DNA repair in bacteria

Author: Bharati, Binod K., Gowder, Manjunath, Zheng, Fangfang, Alzoubi, Khaled, Svetlov, Vladimir, Kamarthapu, Venu, Weaver, Jacob W., Epshtein, Vitaly, Vasilyev, Nikita, Shen, Liqiang, Zhang, Yu, Nudler, Evgeny

Issue&Volume: 2022-03-30

Abstract: Transcription-coupled DNA repair (TCR) is presumed to be a minor sub-pathway of nucleotide excision repair (NER) in bacteria. Global genomic repair is thought to perform the bulk of repair independently of transcription. TCR is also believed to be mediated exclusively by Mfd—a DNA translocase of a marginal NER phenotype1,2,3. Here we combined in cellulo cross-linking mass spectrometry with structural, biochemical and genetic approaches to map the interactions within the TCR complex (TCRC) and to determine the actual sequence of events that leads to NER in vivo. We show that RNA polymerase (RNAP) serves as the primary sensor of DNA damage and acts as a platform for the recruitment of NER enzymes. UvrA and UvrD associate with RNAP continuously, forming a surveillance pre-TCRC. In response to DNA damage, pre-TCRC recruits a second UvrD monomer to form a helicase-competent UvrD dimer that promotes backtracking of the TCRC. The weakening of UvrD–RNAP interactions renders cells sensitive to genotoxic stress. TCRC then recruits a second UvrA molecule and UvrB to initiate the repair process. Contrary to the conventional view, we show that TCR accounts for the vast majority of chromosomal repair events; that is, TCR thoroughly dominates over global genomic repair. We also show that TCR is largely independent of Mfd. We propose that Mfd has an indirect role in this process: it participates in removing obstructive RNAPs in front of TCRCs and also in recovering TCRCs from backtracking after repair has been completed.

DOI: 10.1038/s41586-022-04530-6

Source: https://www.nature.com/articles/s41586-022-04530-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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