A common single nucleotide polymorphism in human diseases alters the orientation of microprocessor complex on pri-mir-146a

Abstract

The biosynthesis of miRNAs is initiated by the cleavages of the Microprocessor complex on primary miRNA transcripts (pri-miRNAs). Microprocessor consists of DROSHA which is an RNAse III enzyme and its cofactor, DGCR8. The complex can orient on pri-miRNAs in two directions that produce productive and unproductive cleavages. However, only the productive orientation in which DROSHA and DGCR8 bind to the basal and apical junctions, respectively, results in miRNA synthesis. In contrast, the swapping orientation of DROSHA and DGCR8 destroys miRNA sequences. rs2910164 (G>C), a functional single nucleotide polymorphism (SNP) occurred in pri-mir-146a, is associated with numerous human diseases including hepatocellular carcinoma, gastric cancer, breast cancer, thyroid carcinogenesis, ankylosing spondylitis, colorectal cancer, and cervical cancer. Although this G>C SNP was found to cause reduced cellular miR-146a expression, it remains elusive if this small change disrupts Microprocessor activity. In this study, we found that the G>C SNP generates an unexpected high-scored mGHG motif in the upper stem of the pri-mir-146a-C variant and therefore recruits DROSHA to its apical junction. Thus, the SNP enhances unproductive cleavages that lead to the depletion of miR-146a level. Our findings help uncover the molecular mechanism by which the disease-related SNP alters the production of mature miR-146a and thereby modulates its biological functions.

Date of Award	2021
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Tuan Anh NGUYEN (Supervisor)