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.

MiR-19b non-canonical binding is directed by HuR and confers chemosensitivity through regulation of P-glycoprotein in breast cancer

“…Regulation of ABCB1 by HuR is further supported by the fact that it has previously been identified as a direct HuR target using pull-down and sequencing approaches (Mukherjee et al, 2011). MiR-19b has been implicated as a potential oncomiR in many cancers (Olive et al, 2009, Jin et al, 2013, and it has been assigned potential cancer-promoting functions in breast cancer via negative regulation of tumour suppressor genes such as PTEN (Li et al, 2014), PTPRG (Liu et al, 2016) and BRCA2 (Mogilyansky et al, 2016). In contrast, our data support a tumour suppressor role for miR-19b in breast epithelial cells, in accordance with some data in prostate cancer (Ottman et al, 2016) and hepatocellular carcinoma (Hung et al, 2015).…”

Integrated analysis of long noncoding RNA and mRNA expression profiles reveals the potential role of long noncoding RNA in different bovine lactation stages

“…Generally, nonprotein coding RNA are defined by the size of mature transcripts, which includes small/ short nonprotein coding RNA (<200 nucleotides) and long noncoding RNA (lncRNA; >200 nucleotides). Micro RNA (miRNA) are the most widely known small/short nonprotein coding RNA and are known to regulate the expression of targeted genes (Gindin et al, 2015;Mogilyansky et al, 2016). In the past few years research interest on lncRNA has rapidly emerged and, accordingly, an increasing number of lncRNA have been revealed in different species, including Homo sapiens (McHugh et al, 2015), rat (Gopalakrishnan et al, 2015), goat (Ren et al, 2016), pig , chicken (He et al, 2016), and bovine (Sun et al, 2016).…”

“A Proteogenomic workflow reveals distinct molecular phenotypes related to breast cancer appearance”

“…Here we discovered that proteins involved in processes such as splicing and translational regulation tend to correlate poorly with their transcripts, as opposed to those belonging to immune-related pathways. In this case, cellular processes controlling cellular turnover such as ubiquitination and proteasomal degradation (Kim et al, 2011), miRNA activity (Mogilyansky et al, 2016;Lorenzo-Martín et al, 2019), or epigenetic factors, may actually be responsible for these quantitative discrepancies and target specific protein clusters. The relatively low number of negatively correlated protein-transcript pairs suggest that posttranslational regulation might indeed target specific protein groups, but that the impact on the entire proteome might not be as extensive as previously thought .…”