Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8

doi:10.1093/nar/gkac184

	Molecular basis for human mitochondrial tRNA m(3)C modification by alternatively spliced METTL8
	Huang, Meng-Han 1; Peng, Gui-Xin1,3 ; Mao, Xue-Ling 1; Wang, Jin-Tao 1; Zhou, Jing-Bo 1; Zhang, Jian-Hui 1; Chen, Meirong 2; Wang, En-Duo1,3 ; Zhou, Xiao-Long 1
	2022-04-22
发表期刊	NUCLEIC ACIDS RESEARCH (IF:16.6[JCR-2023],16.1[5-Year])
ISSN	0305-1048
EISSN	1362-4962
卷号	50 期号:7
发表状态	已发表
DOI	10.1093/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
引用统计	被引频次：31[WOS] [WOS记录] [WOS相关记录]
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
推荐引用方式 GB/T 7714	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).