| Literature DB >> 26774475 |
Young Eun Choi1, Khyati Meghani1, Marie-Eve Brault1, Lucas Leclerc1, Yizhou J He1, Tovah A Day2, Kevin M Elias3, Ronny Drapkin4, David M Weinstock2, Fanny Dao5, Karin K Shih5, Ursula Matulonis2, Douglas A Levine5, Panagiotis A Konstantinopoulos6, Dipanjan Chowdhury7.
Abstract
High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.Entities:
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Year: 2016 PMID： 26774475 PMCID： PMC4731274 DOI： 10.1016/j.celrep.2015.12.046
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423