Khalid Ouararhni, Flore Mietton, Jamal S M Sabir, Abdulkhaleg Ibrahim, Annie Molla, Raed S Albheyri, Ali T Zari, Ahmed Bahieldin, Hervé Menoni, Christian Bronner, Stefan Dimitrov, Ali Hamiche
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The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin.</p><p><strong>Conclusions: </strong>Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368025/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of a novel DNA oxidative damage repair pathway, requiring the ubiquitination of the histone variant macroH2A1.1.\",\"authors\":\"Khalid Ouararhni, Flore Mietton, Jamal S M Sabir, Abdulkhaleg Ibrahim, Annie Molla, Raed S Albheyri, Ali T Zari, Ahmed Bahieldin, Hervé Menoni, Christian Bronner, Stefan Dimitrov, Ali Hamiche\",\"doi\":\"10.1186/s12915-024-01987-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. 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引用次数: 0
摘要
背景:组蛋白变体macroH2A(mH2A)是最离经叛道的变体,它比传统的组蛋白H2A大三倍,由一个类似组蛋白H2A的结构域和一个大的非组蛋白区域融合而成,负责将PARP-1招募到染色质上。现有数据表明,组蛋白变体 mH2A 参与了转录调控、异染色质的维持、NAD+ 代谢和双链 DNA 修复:在这里,我们描述了 mH2A 的一种新功能,即通过 PARP-1 参与 DNA 氧化损伤修复。在 DNA 氧化损伤诱导后,mH2A 的耗竭会影响修复和细胞存活。PARP-1 在体内与 mH2A 核小体形成特异性复合物。与 mH2A 核糖体结合的 PARP-1 没有活性。氧化损伤后,mH2A 被泛素化,PARP-1 从 mH2A 核糖体复合物中释放出来并被激活。在没有任何氧化损伤的情况下,活体诱导的 mH2A 泛素化足以释放 PARP-1。然而,用DNA烷化剂MMS或多柔比星处理细胞时,均未观察到PARP-1的释放:我们的数据确定了一种新的 DNA 氧化损伤修复途径,需要 mH2A 泛素化才能使 PARP-1 从染色质中释放并激活。
Identification of a novel DNA oxidative damage repair pathway, requiring the ubiquitination of the histone variant macroH2A1.1.
Background: The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. The available data suggest that the histone variant mH2A participates in the regulation of transcription, maintenance of heterochromatin, NAD+ metabolism, and double-strand DNA repair.
Results: Here, we describe a novel function of mH2A, namely its implication in DNA oxidative damage repair through PARP-1. The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin.
Conclusions: Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation.
期刊介绍:
BMC Biology is a broad scope journal covering all areas of biology. Our content includes research articles, new methods and tools. BMC Biology also publishes reviews, Q&A, and commentaries.