U1 snRNP suppresses microRNA biogenesis by alternative intronic polyadenylation in melanoma

Activation of intronic polyadenylation signals results in premature cleavage and polyadenylation (PCPA). The majority of mammalian microRNAs (miRNAs) are also located within intronic regions of protein-coding genes and are transcriptionally co-expressed with their host genes. Here we show that U1-dependent PCPA by an RNA surveillance mechanism termed telescripting dysregulates miRNA biogenesis in melanoma. When U1 is reduced, miR-211 levels are decreased as a direct consequence of activation of a newly identified alternative intronic polyadenylation signal located upstream of miR-211 within its host gene, the cation channel TRPM1. Various melanoma cell lines revealed decreased U1 levels and a shift from full-length to truncated TRPM1 isoforms with concomitant decreased miR-211 expression. Modulation of TRPM1 alternative polyadenylation (APA) by antisense morpholino oligonucleotides inhibits and potentially restores miR-211 expression to endogenous levels. This mechanism of intronic PCPA and its effects on miRNA biogenesis represents a previously unrecognized additional layer of gene expression regulation suitable for therapeutic modulation when dysregulated as shown for human melanoma.