SRSF3 shapes miR-17-92 cluster to control selective miRNA processing in colorectal cancer

MicroRNA (miRNA) biogenesis is tightly regulated to maintain distinct miRNA expression patterns during development and in adult tissues, dysregulation of miRNAs being a critical determinant of disease. Almost a half of miRNAs in mammalian cells are generated from polycistronic primary transcripts encoding multiple miRNAs but it is enigmatic how the levels of individual miRNAs residing within clusters is controlled. The RNA binding protein SRSF3 (Serine-arginine rich splicing factor 3) has been shown to promote miRNA processing through its binding to CNNC motifs downstream of Drosha cleavage sites. Here we demonstrate that in pluripotent and cancer cells SRSF3 binds to multiple positions along the polycistronic miR-17-92 to specifically enhance the processing of two paralog miRNAs, miR-17 and miR-20a, through its RS domain interactions that alter the pri-miRNA structure. The SRSF3-mediated increase in miR-17/20a levels inhibits the mRNA encoding the cell cycle inhibitor p21 and ultimately promotes the self-renewal properties of both normal and cancer cells. Strikingly, SRSF3-miR-17-92-p21 pathway operates in colorectal cancer cells and is strongly associated with poorly differentiated high grade colorectal tumours, suggesting a direct link between SRSF3-mediated pri-miRNA structure and cancer pathogenesis.