Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b

• Published in: Frontiers in genetics Vol. 7; p. 143
• Main Authors: Mogilyansky, Elena, Clark, Peter, Quann, Kevin, Zhou, Honglei, Londin, Eric, Jing, Yi, Rigoutsos, Isidore
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 31.08.2016
• Subjects: BRCA1; BRCA2; Cancer; DNA Repair; Genetics; MicroRNA (miRNA); post-transcriptional regulation; the miR-17/92 cluster; post-transcriptional regulation; microRNA; cancer; BRCA2; DNA repair; miR-19a; miR-19b
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2016.00143

Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of 'BRCAness.' The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype. Here, we examine the post-transcriptional effects that some members of the six-miRNA cluster known as the miR-17/92 cluster have on the abundance of BRCA2's messenger RNA (mRNA) and protein. We discuss two interactions involving the miR-19a and miR-19b members of the cluster and the 3'UTR of BRCA2's mRNA. We investigated these miRNA:mRNA interactions in 15 cell lines derived from pancreatic, breast, colon, and kidney tissue. We show that over-expression of these two miRNAs results in a concomitant decrease of BRCA2's mRNA and protein expression in a subset of the tested cell lines. Additionally, using luciferase reporter assays we identified direct interactions between miR-19a/miR-19b and a miRNA response element (MRE) in BRCA2's 3'UTR. Our results suggest that BRCA2 is subject to a complex post-transcriptional regulatory program that has specific dependencies on the genetic and phenotypic background of cell types.