Human RNA Methyltransferase BCDIN3D Regulates MicroRNA Processing

SummaryMicroRNAs (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.

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► BCDIN3D is a RNA-methyltransferase that phospho-dimethylates 5′ monophosphate ends
► BCDIN3D targets in vitro and in vivo precursors of miRNAs such as miR-145 and 23b
► Phospho-dimethylation of pre-miR145 impairs its processing by Dicer in vitro
► Depletion of BCDIN3D suppresses tumorigenic phenotypes of breast cancer cell lines