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Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8.

Authors :
Huang MH
Peng GX
Mao XL
Wang JT
Zhou JB
Zhang JH
Chen M
Wang ED
Zhou XL
Source :
Nucleic acids research [Nucleic Acids Res] 2022 Apr 22; Vol. 50 (7), pp. 4012-4028.
Publication Year :
2022

Abstract

METTL8 has recently been identified as the methyltransferase catalyzing 3-methylcytidine biogenesis at position 32 (m3C32) 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 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.<br /> (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Details

Language :
English
ISSN :
1362-4962
Volume :
50
Issue :
7
Database :
MEDLINE
Journal :
Nucleic acids research
Publication Type :
Academic Journal
Accession number :
35357504
Full Text :
https://doi.org/10.1093/nar/gkac184