METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation

被引:360
作者
Pandolfini, Luca [1 ,2 ]
Barbieri, Isaia [1 ,2 ,3 ]
Bannister, Andrew J. [1 ,2 ]
Hendrick, Alan [4 ]
Andrews, Byron [4 ]
Webster, Natalie [4 ]
Murat, Pierre [5 ,8 ]
Mach, Pia [1 ,2 ]
Brandi, Rossella [6 ]
Robson, Samuel C. [1 ,2 ,9 ]
Migliori, Valentina [1 ,2 ]
Alendar, Andrej [1 ,2 ]
d'Onofrio, Mara [6 ,7 ]
Balasubramanian, Shankar [5 ]
Kouzarides, Tony [1 ,2 ]
机构
[1] Univ Cambridge, Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN, England
[2] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QN, England
[3] Univ Cambridge, Addenbrokes Hosp, Dept Pathol, Div Cellular & Mol Pathol, Cambridge CB2 0QQ, England
[4] Storm Therapeut Ltd, Moneta Bldg B280,Babraham Res Campus, Cambridge CB22 3AT, England
[5] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England
[6] Fdn EBRI Rita Levi Montalcini, Genom Lab, Viale Regina Elena 295, I-00161 Rome, Italy
[7] CNR, IFT, Via Fosso Cavaliere 100, I-00133 Rome, Italy
[8] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England
[9] Univ Portsmouth, Sch Pharm & Biomed Sci, St Michaels Bldg,White Swan Rd, Portsmouth PO1 2DT, Hants, England
基金
欧盟地平线“2020”; 英国惠康基金; 欧洲研究理事会;
关键词
MESSENGER-RNA; RIBOSOMAL-RNA; MIRNA; EXPRESSION; LIN28; PSEUDOURIDYLATION; QUADRUPLEXES; TRANSLATION; PATHWAY; COMPLEX;
D O I
10.1016/j.molcel.2019.03.040
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1278 / +
页数:22
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