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J Clin Invest. 2018 Jan 2;128(1):500-516. doi: 10.1172/JCI92742. Epub 2017 Dec 11.

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy.

Author information

1
Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
2
Institute for Systems Biology, Seattle, Washington, USA.
3
Department of Hematology and Medical Oncology.
4
Department of Pathology and Laboratory Medicine.
5
Department of Medicine, and.
6
Department of Biochemistry, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.

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.

KEYWORDS:

Cancer; Cell Biology

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