Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28398198.
- Also identified by DOI 10.7554/eLife.21350 and PMC identifier 5432210.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of <i>BRCA1</i>-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance. Importantly, our results also demonstrate that the BRCA1-PALB2 interaction dictates the choice between HR and SSA. These studies establish functional and mutational landscapes of BRCA1 for HDR and therapy resistance, while revealing novel insights into BRCA1 regulatory mechanisms and HDR pathway choice.
Medical subject headings
- BRCA1 Protein
- DNA Breaks, Double-Stranded
- DNA Repair
- Mutant Proteins