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- W2775609536 abstract "DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ. Mcl-1 also promoted DNA resection mediated by the Mre11 complex and HR-dependent DSB repair. Using the Mcl-1 BH1 domain as a docking site, we identified a small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair, leading to sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcomes." @default.
- W2775609536 created "2017-12-22" @default.
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- W2775609536 date "2017-12-11" @default.
- W2775609536 modified "2023-10-17" @default.
- W2775609536 title "Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy" @default.
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- W2775609536 cites W1979248048 @default.
- W2775609536 cites W1979385111 @default.
- W2775609536 cites W1981816841 @default.
- W2775609536 cites W1982254984 @default.
- W2775609536 cites W1984919526 @default.
- W2775609536 cites W1985679430 @default.
- W2775609536 cites W1996931025 @default.
- W2775609536 cites W2001842836 @default.
- W2775609536 cites W2003472128 @default.
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- W2775609536 cites W2037004712 @default.
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- W2775609536 cites W2062133747 @default.
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- W2775609536 cites W2146204567 @default.
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- W2775609536 doi "https://doi.org/10.1172/jci92742" @default.
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