title: Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance.
abstract: BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect ofBRCA1-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.
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Anantha
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Simhadri
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Tzeh Keong
authors.identifier: 0000-0003-0168-7054
authors.initials: TK
authors.lastname: Foo
authors.affiliation: Department of Genetics, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, United States.
authors.forename: Susanna
authors.initials: S
authors.lastname: Miao
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Liu
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Zhiyuan
authors.identifier: 0000-0003-2834-0309
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Radiation Oncology, Rutgers, The State University of New Jersey, New Brunswick, United States.|Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States.
authors.forename: Bing
authors.identifier: 0000-0003-3259-6139
authors.initials: B
authors.lastname: Xia
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism*; D020029:Base Pairing; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D059765:Homologous Recombination; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D010793:Phthalazines / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050505:Mutant Proteins; D010793:Phthalazines; D010879:Piperazines; D002945:Cisplatin; C531550:olaparib
keywords: BRCA1; BRCA2; PALB2; cancer biology; chromosomes; genes; homologous recombination; human; olaparib; single strand annealing