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Mol Cell. 2019 Apr 19. pii: S1097-2765(19)30269-2. doi: 10.1016/j.molcel.2019.03.040. [Epub ahead of print]

METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation.

Author information

1
The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
2
The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbroke's Hospital, Cambridge CB2 0QQ, UK.
3
Storm Therapeutics, Ltd., Moneta Building (B280), Babraham Research Campus, Cambridge CB22 3AT, UK.
4
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
5
Fondazione EBRI Rita Levi-Montalcini, Genomics Laboratory, Viale Regina Elena 295, 00161 Rome, Italy.
6
Fondazione EBRI Rita Levi-Montalcini, Genomics Laboratory, Viale Regina Elena 295, 00161 Rome, Italy; IFT-CNR, Via del Fosso del Cavaliere 100, 00133 Rome, Italy.
7
The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. Electronic address: tony.kouzarides@gurdon.cam.ac.uk.

Abstract

7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.

KEYWORDS:

7-methylguanosine; G-quadruplexes; METTL1; RNA methylation; SAM-dependent methyltransferase; cell migration; high-throughput sequencing; let-7; miRNA biogenesis; microRNA

PMID:
31031083
DOI:
10.1016/j.molcel.2019.03.040
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