title: Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b.
abstract: 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.
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Mogilyansky
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Clark
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Quann
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Honglei
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Londin
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA.
authors.forename: Isidore
authors.initials: I
authors.lastname: Rigoutsos
keywords: BRCA2; DNA repair; cancer; miR-19a; miR-19b; microRNA; post-transcriptional regulation; the miR-17/92 cluster