DNA甲基转移酶1通过桥接m5C RNA甲基化调节线粒体功能

IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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
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引用次数: 0

摘要

DNA甲基转移酶1 (DNMT1)是一种已知的DNA甲基化维持酶。其复制焦点靶向序列(RFTS)结构域的点突变可导致晚发性神经变性,如常染色体显性小脑性共济失调-耳聋和嗜睡症(ADCA-DN)障碍。在这里,我们证明DNMT1具有结合mRNA转录本的能力,并通过募集NOP2/Sun RNA甲基转移酶2 (NSUN2)促进5-甲基胞嘧啶(m5C) RNA甲基化。反过来,RNA m5C甲基化促进了那些调节线粒体功能的基因的RNA稳定性。当DNMT1 RFTS结构域在小鼠中发生突变时,它会引发DNMT1-RNA的异常相互作用,并显著提高部分代谢基因的m5C RNA甲基化和RNA稳定性。因此,代谢RNA转录物水平升高导致累积氧化应激、线粒体功能障碍和神经系统症状。总之,我们的研究结果揭示了DNMT1在调节DNA和RNA甲基化中的双重作用,这进一步调节了线粒体功能,揭示了DNMT1突变诱导的神经变性的致病机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation

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.
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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
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.
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