title: Critical role of monoubiquitination of histone H2AX protein in histone H2AX phosphorylation and DNA damage response.
abstract: DNA damage response is an important surveillance mechanism used to maintain the integrity of the human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 upon genotoxic stress, which provides a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Here, we show that monoubiquitination of H2AX is induced upon DNA double strand breaks and plays a critical role in H2AX Ser-139 phosphorylation (γ-H2AX), in turn facilitating the recruitment of MDC1 to DNA damage foci. Mechanistically, we show that monoubiquitination of H2AX induced by RING finger protein 2 (RNF2) is required for the recruitment of active ataxia telangiectasia mutated to DNA damage foci, thus affecting the formation of γ-H2AX. Importantly, a defect in monoubiquitination of H2AX profoundly enhances ionizing radiation sensitivity. Our study therefore suggests that monoubiquitination of H2AX is an important step for DNA damage response and may have important clinical implications for the treatment of cancers.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Chinese Medicine, Kaohsiung 833, Taiwan; Graduate Institute of Clinical Medical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. Electronic address: hkang3@adm.cgmh.org.tw.
authors.forename: Hong-Yo
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Wei-Lei
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Betty
authors.initials: B
authors.lastname: Lamothe
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Campos
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030. Electronic address: hklin@mdanderson.org.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D006657:Histones / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011839:Radiation, Ionizing; D015398:Signal Transduction; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006657:Histones; D025801:Ubiquitin; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse