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

• Type of Material: Article
• Authors: Guo Chen, Emory University; Andrew T. Magis, Institute for Systems Biology; Ke Xu, Emory University; Dongkyoo Park, Emory University; David Yu, Emory University; Taofeek K Owonikoko, Emory University; Gabriel Sica, Emory University; Sarah Satola, Emory University; Suresh S Ramalingam, Emory University; Walter J Curran, Emory University; Paul Doetsch, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2018-01-02
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2018, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI92742
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 128
• Issue: 1
• Start Page: 500
• End Page: 516
• Grant/Funding Information: This work was supported by NIH/NCI grants R01CA193828, R01CA136534, and R01CA200905 (to XD) and R01CA178999 (to DSY); by the Winship Research Pathology and Integrated Cellular Imaging shared resource and the Emory Comprehensive Glycomics Core supported by the Winship Cancer Institute of Emory University (P30CAJ 38292); by the Winship Fashion a Cure Research Scholar Award (to XD), a philanthropic award provided by the Winship Cancer Institute of Emory University; and by the Winship Endowment Fund (to XD).
• Keywords: Science & Technology; HOMOLOGOUS RECOMBINATION; ISOTHERMAL TITRATION CALORIMETRY; MAMMALIAN-CELLS; DAMAGE RESPONSE; CTIP; Medicine, Research & Experimental; RESECTION; REPAIR PATHWAY CHOICE; END-JOINING PATHWAY; Life Sciences & Biomedicine; DOUBLE-STRAND-BREAK; Research & Experimental Medicine; PROTEIN
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pathology; Health Sciences, Oncology

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/G 2 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.