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.
Cell. 2012 Oct 12;151(2):278-88. doi: 10.1016/j.cell.2012.08.041.
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.
微小 RNA（miRNAs）调节关键的生物过程，其异常表达可能导致癌症。典型 miRNA 的初级转录物被 RNase III 酶 Drosha 和 Dicer 顺序切割，产生 5'单磷酸末端，这对于随后的 miRNA 功能很重要。特别是，Dicer 对 pre-miRNAs 的 5'单磷酸的识别对于 miRNA 精确有效的生物发生很重要。在这里，我们鉴定了一种 RNA-甲基转移酶 BCDIN3D，它对这个 5'单磷酸进行 O-甲基化，并负调控 miRNA 成熟。具体来说，我们表明 BCDIN3D 在体外和体内磷酸二甲基化 pre-miR-145，并且磷酸二甲基化的 pre-miR-145 在体外显示出由 Dicer 处理减少。一致地，BCDIN3D 的耗竭导致乳腺癌细胞中 pre-miR-145 水平降低，同时成熟 miR-145 水平升高，从而抑制它们的肿瘤表型。总之，我们的结果揭示了一种可能参与癌症的 miRNA 甲基化途径，该途径拮抗 Dicer 依赖性的 miR-145 以及其他 miRNAs 的加工。
