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ppGpp 对转录延伸和 DNA 修复的控制。

Control of transcription elongation and DNA repair by alarmone ppGpp.

机构信息

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.

Engelhardt Institute of Molecular Biology, Russian Academy of Science, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Moscow, Russia.

出版信息

Nat Struct Mol Biol. 2023 May;30(5):600-607. doi: 10.1038/s41594-023-00948-2. Epub 2023 Mar 30.

DOI:10.1038/s41594-023-00948-2
PMID:36997761
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10191844/
Abstract

Second messenger (p)ppGpp (collectively guanosine tetraphosphate and guanosine pentaphosphate) mediates bacterial adaptation to nutritional stress by modulating transcription initiation. More recently, ppGpp has been implicated in coupling transcription and DNA repair; however, the mechanism of ppGpp engagement remained elusive. Here we present structural, biochemical and genetic evidence that ppGpp controls Escherichia coli RNA polymerase (RNAP) during elongation via a specific site that is nonfunctional during initiation. Structure-guided mutagenesis renders the elongation (but not initiation) complex unresponsive to ppGpp and increases bacterial sensitivity to genotoxic agents and ultraviolet radiation. Thus, ppGpp binds RNAP at sites with distinct functions in initiation and elongation, with the latter being important for promoting DNA repair. Our data provide insights on the molecular mechanism of ppGpp-mediated adaptation during stress, and further highlight the intricate relationships between genome stability, stress responses and transcription.

摘要

第二信使（p）ppGpp（鸟苷四磷酸和鸟苷五磷酸的统称）通过调节转录起始来介导细菌对营养胁迫的适应。最近，ppGpp 被牵连到转录和 DNA 修复的偶联中；然而，ppGpp 的结合机制仍然难以捉摸。在这里，我们提出了结构、生化和遗传证据，表明 ppGpp 在延伸过程中通过一个在起始过程中不起作用的特定位点来控制大肠杆菌 RNA 聚合酶（RNAP）。结构导向的突变使延伸（而不是起始）复合物对 ppGpp 无反应，并增加了细菌对遗传毒性剂和紫外线辐射的敏感性。因此，ppGpp 在起始和延伸中结合 RNAP 的位点具有不同的功能，后者对于促进 DNA 修复很重要。我们的数据为应激过程中 ppGpp 介导的适应的分子机制提供了深入了解，并进一步强调了基因组稳定性、应激反应和转录之间的复杂关系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/7363d23fa2b3/41594_2023_948_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/7363d23fa2b3/41594_2023_948_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/db01b61d4ddb/41594_2023_948_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/dd2cd1cd6493/41594_2023_948_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/cb61df835a71/41594_2023_948_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/525d70f554f8/41594_2023_948_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/a009df6509ea/41594_2023_948_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/66638bf5d325/41594_2023_948_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/acf0c794a33a/41594_2023_948_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/f82cffa55150/41594_2023_948_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/116165f69c4a/41594_2023_948_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3235/10191844/7363d23fa2b3/41594_2023_948_Fig12_ESM.jpg

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