小柯机器人

英国谢菲尔德大学Sherif F. El-Khamisy研究团队发现基因调控元件上氧化损伤修复的一种机制。2022年9月28日出版的《自然》杂志发表了这项成果。

研究人员表明启动子是通过核有丝分裂器蛋白NuMA（也称为NUMA1）介导的过程来保护免受氧化损伤。NuMA在转录起始点周围约100bp处表现出基因组占据。它与RNA聚合酶II的起始形式、暂停释放因子和单链断裂修复（SSBR）组件（如TDP1）结合。在氧化损伤后，染色质上的结合会增加，NuMA促进了TDP1在受损染色质上的富集。NuMA的耗尽会增加启动子的氧化损伤。NuMA通过限制RNA聚合酶II的聚ADP-核糖基化来促进转录，增加其可用性和在启动子上暂停的释放。

新生RNA的代谢标记确定了依赖NuMA进行转录的基因，包括即时早期反应基因。用介导与SSBR结合的突变体或有丝分裂功能的突变体来补充NuMA缺陷的细胞可恢复SSBR缺陷。这些发现强调了基因调控元件上氧化性DNA损伤修复的重要性，并描述了一个履行这一功能的过程。

据悉，氧化性基因组损伤是细胞代谢不可避免的结果。在转录激活过程中，它通过表观遗传学去甲基化在基因调控元件上产生。

附：英文原文

Title: A mechanism for oxidative damage repair at gene regulatory elements

Author: Ray, Swagat, Abugable, Arwa A., Parker, Jacob, Liversidge, Kirsty, Palminha, Nelma M., Liao, Chunyan, Acosta-Martin, Adelina E., Souza, Cleide D. S., Jurga, Mateusz, Sudbery, Ian, El-Khamisy, Sherif F.

Issue&Volume: 2022-09-28

Abstract: Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate–early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.

DOI: 10.1038/s41586-022-05217-8

Source: https://www.nature.com/articles/s41586-022-05217-8

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
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