Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction |
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| Affiliation: | 1. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA;2. Protein Production Facility, St. Jude Children’s Research Hospital, Memphis, TN, USA;3. School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan;1. Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;2. Clinical Microbiology, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;3. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;1. The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, United States;2. Indiana University School of Medicine, Indianapolis, IN 46202, United States;1. Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Japan;2. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan;1. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA;2. Protein Production Facility, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA;3. School of Life Sciences, Tianjin University, Tianjin 300072, China;4. Department of Molecular Biology, Ariel University, Ariel 40700, Israel |
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| Abstract: | DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure–activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR. |
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| Keywords: | Interstrand crosslink repair DNA damage response REV7 REV3L Polζ Chemotherapy High-throughput screening |
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