Human RNA methyltransferase BCDIN3D regulates microRNA processing.
MicroRNAs (miRNAs) regulate key biological processes and their aberrant expression may lead to cancer. The primary transcript of canonical miRNAs is sequentially cleaved by the RNase III enzymes, Drosha and Dicer, which generate 5' monophosphate ends that are important for subsequent miRNA functions. In particular, the recognition of the 5' monophosphate of pre-miRNAs by Dicer is important for precise and effective biogenesis of miRNAs. Here, we identify a RNA-methyltransferase, BCDIN3D, that O-methylates this 5' monophosphate and negatively regulates miRNA maturation. Specifically, we show that BCDIN3D phospho-dimethylates pre-miR-145 both in vitro and in vivo and that phospho-dimethylated pre-miR-145 displays reduced processing by Dicer in vitro. Consistently, BCDIN3D depletion leads to lower pre-miR-145 and concomitantly increased mature miR-145 levels in breast cancer cells, which suppresses their tumorigenic phenotypes. Together, our results uncover a miRNA methylation pathway potentially involved in cancer that antagonizes the Dicer-dependent processing of miR-145 as well as other miRNAs.
Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Blerta
B
Xhemalce
Samuel C
SC
Robson
Tony
T
Kouzarides
D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000378:metabolism
C541010:MIRN145 microRNA, human; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C547279:MePCE protein, human; D008780:Methyltransferases; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases