{"title":"DNA甲基转移酶1通过桥接m5C RNA甲基化调节线粒体功能","authors":"Jing Wang, Xiaoqian Deng, Tianshen Jian, Shanshan Yin, Linzhi Chen, Laurent Vergnes, Zhehao Li, Huoyuan Liu, Ryan Lee, Sin Yee Lim, Jae Hoon Bahn, Xinshu Xiao, Xianmin Zhu, Ganlu Hu, Karen Reue, Yizhi Liu, Guoping Fan","doi":"10.1016/j.molcel.2025.04.019","DOIUrl":null,"url":null,"abstract":"DNA methyltransferase 1 (DNMT1) is an enzyme known for DNA methylation maintenance. Point mutations in its replication focus targeting sequence (RFTS) domain lead to late-onset neurodegeneration, such as autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) disorder. Here, we demonstrated that DNMT1 has the capability to bind to mRNA transcripts and facilitate 5-methylcytosine (m<sup>5</sup>C) RNA methylation by recruiting NOP2/Sun RNA methyltransferase 2 (NSUN2). RNA m<sup>5</sup>C methylation, in turn, promotes RNA stability for those genes modulating mitochondrial function. When the DNMT1 RFTS domain is mutated in mice, it triggers aberrant DNMT1-RNA interaction and significantly elevated m<sup>5</sup>C RNA methylation and RNA stability for a portion of metabolic genes. Consequently, increased levels of metabolic RNA transcripts contribute to cumulative oxidative stress, mitochondrial dysfunction, and neurological symptoms. Collectively, our results reveal a dual role of DNMT1 in regulating both DNA and RNA methylation, which further modulates mitochondrial function, shedding light on the pathogenic mechanism of DNMT1 mutation-induced neurodegeneration.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"18 1","pages":""},"PeriodicalIF":16.6000,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation\",\"authors\":\"Jing Wang, Xiaoqian Deng, Tianshen Jian, Shanshan Yin, Linzhi Chen, Laurent Vergnes, Zhehao Li, Huoyuan Liu, Ryan Lee, Sin Yee Lim, Jae Hoon Bahn, Xinshu Xiao, Xianmin Zhu, Ganlu Hu, Karen Reue, Yizhi Liu, Guoping Fan\",\"doi\":\"10.1016/j.molcel.2025.04.019\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"DNA methyltransferase 1 (DNMT1) is an enzyme known for DNA methylation maintenance. Point mutations in its replication focus targeting sequence (RFTS) domain lead to late-onset neurodegeneration, such as autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) disorder. Here, we demonstrated that DNMT1 has the capability to bind to mRNA transcripts and facilitate 5-methylcytosine (m<sup>5</sup>C) RNA methylation by recruiting NOP2/Sun RNA methyltransferase 2 (NSUN2). RNA m<sup>5</sup>C methylation, in turn, promotes RNA stability for those genes modulating mitochondrial function. When the DNMT1 RFTS domain is mutated in mice, it triggers aberrant DNMT1-RNA interaction and significantly elevated m<sup>5</sup>C RNA methylation and RNA stability for a portion of metabolic genes. Consequently, increased levels of metabolic RNA transcripts contribute to cumulative oxidative stress, mitochondrial dysfunction, and neurological symptoms. Collectively, our results reveal a dual role of DNMT1 in regulating both DNA and RNA methylation, which further modulates mitochondrial function, shedding light on the pathogenic mechanism of DNMT1 mutation-induced neurodegeneration.\",\"PeriodicalId\":18950,\"journal\":{\"name\":\"Molecular Cell\",\"volume\":\"18 1\",\"pages\":\"\"},\"PeriodicalIF\":16.6000,\"publicationDate\":\"2025-05-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cell\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.molcel.2025.04.019\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2025.04.019","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation
DNA methyltransferase 1 (DNMT1) is an enzyme known for DNA methylation maintenance. Point mutations in its replication focus targeting sequence (RFTS) domain lead to late-onset neurodegeneration, such as autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) disorder. Here, we demonstrated that DNMT1 has the capability to bind to mRNA transcripts and facilitate 5-methylcytosine (m5C) RNA methylation by recruiting NOP2/Sun RNA methyltransferase 2 (NSUN2). RNA m5C methylation, in turn, promotes RNA stability for those genes modulating mitochondrial function. When the DNMT1 RFTS domain is mutated in mice, it triggers aberrant DNMT1-RNA interaction and significantly elevated m5C RNA methylation and RNA stability for a portion of metabolic genes. Consequently, increased levels of metabolic RNA transcripts contribute to cumulative oxidative stress, mitochondrial dysfunction, and neurological symptoms. Collectively, our results reveal a dual role of DNMT1 in regulating both DNA and RNA methylation, which further modulates mitochondrial function, shedding light on the pathogenic mechanism of DNMT1 mutation-induced neurodegeneration.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.