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Determine the Impact of Novel BRCA1 Translation Start Sites on Therapy Resistance in Ovarian Cancer

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Technical Report,01 Jul 2015,30 Jun 2016

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Institute for Cancer Research Philadelphia United States

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Purpose Platinum-based chemotherapy has been the mainstay of ovarian cancer therapy for the past three decades. More recently,polyADP-ribose polymerase PARP inhibitors have emerged as promising agents for the treatment of ovarian cancer. However,similar to platinum, all patients eventually demonstrate tumor progression while being treated with PARP inhibitor therapy, and drug resistance is a major clinical hurdle. The BRCA1 protein is involved in homologous recombination HR DNA repair, and mutations in the BRCA1 gene that render the protein product dysfunctional result in cellular sensitivity to DNA damaging agents. However, therapy resistance often develops. Scope In this proposal, we aimed to characterize N-terminal deficient BRCA1proteins contribution to DNA damage repair and their ability to confer resistance to ovarian cancer therapeutics, as well as identify novel small molecules that specifically kill N-terminal deficient BRCA1 protein expressing cells. Major findings In the reporting period, we generated and expressed a number of BRCA1 proteins produced from downstream translation start sites that were truncated at the N-terminal region and lacked the RING domain. We show that RING deficient-BRCA1 proteins were hypomorphic, contributing to RAD51 loading, PARPi and cisplatin resistance. The mechanism we describe may not be limited to cancers with BRCA1185delAG mutations and could be relevant to multiple frameshifting 5 located BRCA1 mutations. However, mutations located after Met-297 c.891 are unlikely to develop resistance through this mechanism, as we show that the next downstream translation start site at Met-531 c.1593 produced a functionless protein.

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