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Publication Abstract from PubMed

Chemical modifications of RNA have key roles in many biological processes(1-3). N(7)-methylguanosine (m(7)G) is required for integrity and stability of a large subset of tRNAs(4-7). The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types(8-14). Mutations in WDR4 cause human developmental phenotypes including microcephaly(15-17). How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive(18). Here we show, through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the alphaC region of METTL1 transforms into a helix, which together with the alpha6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.

Structural basis of regulated m(7)G tRNA modification by METTL1-WDR4.,Li J, Wang L, Hahn Q, Nowak RP, Viennet T, Orellana EA, Roy Burman SS, Yue H, Hunkeler M, Fontana P, Wu H, Arthanari H, Fischer ES, Gregory RI Nature. 2023 Jan;613(7943):391-397. doi: 10.1038/s41586-022-05566-4. Epub 2023 , Jan 4. PMID:36599985^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.