BRCA1-Dependent Translational Regulation in Breast Cancer Cells

Abstract

BRCA1 (Breast Cancer 1) has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A)-Binding Protein 1) and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets.

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

“…BRCA1 is a tumor suppressor gene which plays a key role in numerous cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. 4 Recent research has confirmed that BRCA1 is an important transcriptional regulator, and BRCA1 -depleted breast cancer cells shows changes to approximately 7% of the mRNAs expressed [4]. Moreover, our recent study also indicated that angiotensin II type 1 receptor and epidermal growth factor receptor displayed different expression patterns in BRCA1 -defective cancer cells [5,6], and confirmed that differential epigenetic regulation of transcription exist along with BRCA1 inactivation [7,8].…”

BRCA1 Mediated Homologous Recombination and S Phase DNA Repair Pathways Restrict LINE-1 Retrotransposition in Human Cells

“…We therefore hypothesized that BRCA1 may inhibit ORF2 translation through direct binding to L1 mRNA in the cytoplasm as such a function has been previously attributed to BRCA1 for several mRNAs and proteins 54 . To evaluate a possible physical interaction between BRCA1 and L1 mRNA, we performed immunoprecipitation of BRCA1 protein followed by RT-qPCR of L1 mRNA.…”

A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer

“…BRCA1 is a tumor suppressor gene that is involved in multiple cellular processes. 5 Recent research has confirmed that BRCA1 is an important transcriptional regulator, and BRCA1 depletion results in changes to approximately 7% of the mRNAs expressed in cancer cells. 5 Our recent study also indicated that there are wide ranges of DNA damage repair, transcriptional regulation, epigenetic patterns, and metabolic differences between cases of BRCA1 dysfunction and the basal phenotype.…”

“…5 Recent research has confirmed that BRCA1 is an important transcriptional regulator, and BRCA1 depletion results in changes to approximately 7% of the mRNAs expressed in cancer cells. 5 Our recent study also indicated that there are wide ranges of DNA damage repair, transcriptional regulation, epigenetic patterns, and metabolic differences between cases of BRCA1 dysfunction and the basal phenotype. [6][7][8][9][10][11][12] Notably, despite ongoing trials of PARP inhibitors in the treatment of BRCA1-related breast cancer.…”