title: The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by the platinum-based anticancer drugs.
abstract: The breast cancer susceptibility protein 1 (BRCA1) participates in the maintenance of cells genomic integrity through DNA repair, cell cycle checkpoint, protein ubiquitination, and transcriptional regulation. The N-terminus of BRCA1 contains a RING domain that preferentially forms a heterodimeric complex with BARD1. The BRCA1-BARD1 RING complex has an E3 ubiquitin ligase activity that plays an essential role in response to DNA damage. Preclinical and clinical studies have recently revealed that structural changes to the heterodimer result in alterations to the BRCA1-mediated DNA repair pathways in cancer cells, and lead to hypersensitivity to several chemotherapeutic agents. It is of interest to approach the BRCA1 RING domain as a potentially molecular target for platinum-based drugs for cancer therapy. A previous study has shown that the anticancer drug cisplatin formed intramolecular and intermolecular BRCA1 adducts in which His117 was the primary platinum-binding site, and conferred conformational changes and induced thermostability. Here, we have studied the functional consequence of the in vitro platination of the BRCA1 RING domain by a number of platinum complexes. The BRCA1 ubiquitin ligase activity was inhibited by transplatin > cisplatin > oxaliplatin > carboplatin in that order. The consequences of the binding of the platinum complexes on the reactivity of the BRCA1 were also discussed. The data raised the possibility of selectively targeting the BRCA1 DNA repair for cancer therapy.
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand.
authors.forename: Apichart
authors.initials: A
authors.lastname: Atipairin
authors.forename: Bhutorn
authors.initials: B
authors.lastname: Canyuk
authors.forename: Adisorn
authors.initials: A
authors.lastname: Ratanaphan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016190:Carboplatin / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000077150:Oxaliplatin; C034697:transplatin; D016190:Carboplatin; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin