Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance
- Rutgers, The State University of New Jersey, United States
Abstract
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-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.
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Author details
Funding
National Cancer Institute (R01CA138804)
- Bing Xia
Congressionally Directed Medical Research Programs (W81XWH-10-1-0486)
- Rachel W Anantha
National Cancer Institute (R01CA188096)
- Bing Xia
National Cancer Institute (R01CA169182)
- Shridar Ganesan
National Cancer Institute (R01CA195612)
- Zhiyuan Shen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Anantha et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance
eLife 6:e21350.
https://doi.org/10.7554/eLife.21350
