Native HMGB1 protein inhibits repair of cisplatin-damaged nucleosomes in vitro |
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| Authors: | Iva Ugrinova Stanislava Zlateva Iliya G Pashev Evdokia A Pasheva |
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| Institution: | 1. Department of Medicine, New York University School of Medicine/New York University Cancer Center, 240 East 38th Street, New York, NY 10016, USA;2. Medicine/Oncology, Stanford Cancer Center, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA 94305, USA;1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;2. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China;3. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China;4. Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China;5. Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China;6. Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China;7. Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA;1. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania;2. Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China;3. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;4. Department of Medicine, University of Chicago, Chicago, Illinois;5. Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York;6. Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York;7. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China;8. Department of Infectious Diseases, State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China;1. Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Brazil;2. Instituto Nacional de Entomologia Molecular, Universidade Federal do Rio de Janeiro, Brazil;3. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, United States |
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| Abstract: | The high mobility group box (HMGB) 1 protein, one of the most abundant nuclear non-histone proteins has been known for its inhibitory effect on repair of DNA damaged by the antitumor drug cisplatin. Here, we report the first results that link HMGB1 to repair of cisplatin-treated DNA at nucleosome level. Experiments were carried out with three types of reconstituted nucleosomes strongly positioned on the damaged DNA: linker DNA containing nucleosomes (centrally and end-positioned) and core particles. The highest repair synthesis was registered with end-positioned nucleosomes, two and three times more efficient than that with centrally positioned nucleosomes and core particles, respectively. HMGB1 inhibited repair of linker DNA containing nucleosomes more efficiently than that of core particles. Just the opposite was the effect of the in vivo acetylated HMGB1: stronger repair inhibition was obtained with core particles. No inhibition was observed with HMGB1 lacking the acidic tail. Binding of HMGB1 proteins to different nucleosomes was also analysed. HMGB1 bound preferentially to damage nucleosomes containing linker DNA, while the binding of the acetylated protein was linker independent. We show that both the repair of cisplatin-damaged nucleosomes and its inhibition by HMGB1 are nucleosome position-dependent events which are accomplished via the acidic tail and modulated by acetylation. |
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