Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8
2022-04-22
发表期刊NUCLEIC ACIDS RESEARCH (IF:16.6[JCR-2023],16.1[5-Year])
ISSN0305-1048
EISSN1362-4962
卷号50期号:7
发表状态已发表
DOI10.1093/nar/gkac184
摘要METTL8 has recently been identified as the methyltransferase catalyzing 3-methylcytidine biogenesis at position 32 (m(3)C32) of mitochondrial tRNAs. METTL8 also potentially participates in mRNA methylation and R-loop biogenesis. How METTL8 plays multiple roles in distinct cell compartments and catalyzes mitochondrial tRNA m(3)C formation remain unclear. Here, we discovered that alternative mRNA splicing generated several isoforms of METTL8. One isoform (METTL8-Iso1) was targeted to mitochondria via an N-terminal pre-sequence, while another one (METTL8-Iso4) mainly localized to the nucleolus. METTL8-Iso1-mediated m(3)C32 modification of human mitochondrial tRNA(Thr) (hmtRNA(Thr)) was not reliant on t(6)A modification at A37 (t(6)A37), while that of hmtRNA(Ser)(UCN) critically depended on i(6)A modification at A37 (i(6)A37). We clarified the hmtRNA(Thr) substrate recognition mechanism, which was obviously different from that of hmtRNA(Ser)(UCN), in terms of requiring a G35 determinant. Moreover, SARS2 (mitochondrial seryl-tRNA synthetase) interacted with METTL8-Iso1 in an RNA-independent manner and modestly accelerated m(3)C modification activity. We further elucidated how nonsubstrate tRNAs in human mitochondria were efficiently discriminated by METTL8-Iso1. In summary, our results established the expression pattern of METTL8, clarified the molecular basis for m(3)C32 modification by METTL8-Iso1 and provided the rationale for the involvement of METTL8 in tRNA modification, mRNA methylation or R-loop biogenesis.
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收录类别SCI ; SCIE
语种英语
资助项目National Key Research and Development Program of China["2017YFA0504000","2021YFA1300800","2021YFC2700903"] ; Natural Science Foundation of China[31822015,81870896,31670801,91940302,32000889] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB19010203] ; Committee of Science and Technology in Shanghai[22ZR1481300] ; Shanghai Key Laboratory of Embryo Original Diseases[Shelab201904]
WOS研究方向Biochemistry & Molecular Biology
WOS类目Biochemistry & Molecular Biology
WOS记录号WOS:000785053800031
出版者OXFORD UNIV PRESS
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/180904
专题生命科学与技术学院_博士生
生命科学与技术学院_特聘教授组_王恩多组
通讯作者Wang, En-Duo; Zhou, Xiao-Long
作者单位
1.Chinese Acad Sci, State Key Lab Mol Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol,Univ Chinese Ac, 320 Yue Yang Rd, Shanghai 200031, Peoples R China
2.China Pharmaceut Univ, Sch Pharm, 639 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Hua Xia Rd, Shanghai 201210, Peoples R China
通讯作者单位生命科学与技术学院
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Huang, Meng-Han,Peng, Gui-Xin,Mao, Xue-Ling,et al. Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8[J]. NUCLEIC ACIDS RESEARCH,2022,50(7).
APA Huang, Meng-Han.,Peng, Gui-Xin.,Mao, Xue-Ling.,Wang, Jin-Tao.,Zhou, Jing-Bo.,...&Zhou, Xiao-Long.(2022).Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8.NUCLEIC ACIDS RESEARCH,50(7).
MLA Huang, Meng-Han,et al."Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8".NUCLEIC ACIDS RESEARCH 50.7(2022).
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