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METTL8 also potentially participates in mRNA methylation and R-loop biogenesis. How METTL8 plays multiple roles in distinct cell compartments and catalyzes mitochondrial tRNA m3C 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 m3C32 modification of human mitochondrial tRNAThr (hmtRNAThr) was not reliant on t6A modification at A37 (t6A37), while that of hmtRNASer(UCN) critically depended on i6A modification at A37 (i6A37). We clarified the hmtRNAThr substrate recognition mechanism, which was obviously different from that of hmtRNASer(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 m3C 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 m3C32 modification by METTL8-Iso1 and provided the rationale for the involvement of METTL8 in tRNA modification, mRNA methylation or R-loop biogenesis.<\/jats:p>","DOI":"10.1093\/nar\/gkac184","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T12:14:18Z","timestamp":1646914458000},"page":"4012-4028","source":"Crossref","is-referenced-by-count":44,"title":["Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8"],"prefix":"10.1093","volume":"50","author":[{"given":"Meng-Han","family":"Huang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Xin","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"},{"name":"School of Life Science and Technology, ShanghaiTech University, 393 Middle Hua Xia Road, Shanghai\u00a0201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Ling","family":"Mao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meirong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing\u00a0211198, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3657-1166","authenticated-orcid":false,"given":"En-Duo","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"},{"name":"School of Life Science and Technology, ShanghaiTech University, 393 Middle Hua Xia Road, Shanghai\u00a0201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3701-5965","authenticated-orcid":false,"given":"Xiao-Long","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai\u00a0200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"2022042200051236900_B1","doi-asserted-by":"crossref","first-page":"e1595","DOI":"10.1002\/wrna.1595","article-title":"Naturally occurring modified ribonucleosides","volume":"11","author":"McCown","year":"2020","journal-title":"Wiley Interdiscip. 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Life Sci."},{"key":"2022042200051236900_B5","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1261\/rna.2653411","article-title":"Actin-binding protein ABP140 is a methyltransferase for 3-methylcytidine at position 32 of tRNAs in saccharomycescerevisiae","volume":"17","author":"Noma","year":"2011","journal-title":"RNA"},{"key":"2022042200051236900_B6","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1261\/rna.2652611","article-title":"A domain of the actin binding protein abp140 is the yeast methyltransferase responsible for 3-methylcytidine modification in the tRNA anti-codon loop","volume":"17","author":"D'Silva","year":"2011","journal-title":"RNA"},{"key":"2022042200051236900_B7","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1038\/s41467-020-16321-6","article-title":"DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification","volume":"11","author":"Lentini","year":"2020","journal-title":"Nat. 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