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The breast cancer susceptibility protein 1 (BRCA1) has been shown to participate in the DNA damage repair pathway.Extensive investigations have revealed the relevance of the BRCA 1-mediated ubiquitination to DNA repair functions.The BRCA1-BARD1 RING complex has an E3 ubiquitin ligase activity that plays an essential role in response to DNA damage.Mutations in the BRCA1 RING domain have resulted in a loss of the E3 ubiquitin ligase activity, and conferred hypersensitivity of the cancer cells to DNA-damaged chemotherapy.Preclinical and clinical studies have recently revealed that structural changes to the RING heterodimer BRCA1-BARD1 result in alterations to the BRCA1-mediated DNA repair pathways in cancer cells, and lead to hypersensitivity to several chemotherapeutic agents.To gain an insight into the functional consequence of the platinated BRCA1, the BRCA1 RING domain protein was in vitro platinated by the anticancer platinum-based complexes.The results showed that the relative E3 ligase activity was inversely proportional to the concentration of the platinum complexes.The BRCA1 E3 ligase activity was inhibited by transplatin > cisplatin > oxaliplatin > carboplatin in that order.The geometry and the properties of both the leaving and the non-leaving groups of the platinum complexes seemed to play essential roles in controlling the reactivity towards BRCA1.In addition, the D67Y BRCA1 RING domain protein exhibited the reduced ubiquitination function,and was more susceptible to cisplatin than the D67E or wild-type BRCA1 RING domain protein.A reduction in BRCA1 E3 ligase activity by the platinum complexes may reflect an alteration of the interaction at the N-terminal RING domains of both BRCA1 and BARD1.Therefore, targeting the BRCA1 RING domain through the disruption of the BRCA1 E3 ligase activity by the platinum-based drugs might be effective for the eradication of the BRCA1-associated cancers and its aggressively basal-like and triple negative subtypes, and the recurrent platinum-resistant cancers with less adverse effects than by the empirical and historical treatments.