Human disease-associated single nucleotide polymorphism changes the orientation of DROSHA on pri-mir-146a

The Microprocessor complex of DROSHA and DGCR8 initiates the biosynthesis of microRNAs (miRNAs) by processing primary miRNAs (pri-miRNAs). The Microprocessor can be oriented on pri-miRNAs in opposite directions to generate productive and unproductive cleavages at their basal and apical junctions, respectively. However, only the productive cleavage gives rise to miRNAs. A single nucleotide polymorphism (SNP, rs2910164) in pri-mir-146a is associated with various human diseases. Although this SNP was found to reduce the expression of miRNA, it is still not known if it affects the activity of the Microprocessor directly, and how it functions. In this study, we revealed that the SNP creates an unexpected mGHG motif at the apical junction of pri-mir-146a. This mGHG motif interacts with the double-stranded RNA-binding domain (dsRBD) of DROSHA, switching its orientation on pri-mir-146a from the basal to the apical junction. As a result, the SNP facilitates Microprocessor to cleave SNP-pri-mir-146a at its unproductive sites. Our findings help to elucidate the molecular mechanism that explains how the disease-associated SNP modulates the biogenesis of pri-mir-146a and thereby affects its cellular functions.