机构：[1]Department of Ophthalmology, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Peking University People's Hospital Beijing, China.[2]Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing, China.[3]Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, China.北京朝阳医院[4]National Institute of Biological Sciences, Beijing, China.[5]Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.[6]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.[7]Department of Ophthalmology and Visual Sciences, Affiliated Dongguan Hospital, Southern Medical University, Guangdong, China.[8]Guangdong Key Laboratory of Genome Stability &Disease Prevention, Shenzhen University School of Medicine, Shenzhen, Guangdong, China.[9]Department of Ophthalmology, Xiamen Eye Center of Xiamen University, Xiamen, China.
Age-related macular degeneration (AMD) is currently the leading cause of blindness worldwide. Previously, we identified ubiquitin-protein ligase E3D (UBE3D) as an AMD-associated protein for East Asian populations, and here we further demonstrate that UBE3D could be associated with DNA damage response.The established I-SceI-inducible GFP reporter system was used to explore the effect of UBE3D on homologous recombination. Immunoprecipitation-mass spectrometry (MS) was used to explore potential UBE3D-interacting proteins and validated with coimmunoprecipitation assays and the pulldown assays. Micrococcal nuclease (MNase) assays were used to investigate the function of UBE3D on heterochromatin de-condensation upon DNA damage. An aged mouse model of blue light-induced eye damage was constructed, and electroretinography (ERG) and optical coherence tomography (OCT) were performed to compare the differences between wild-type and UBE3D+/- mice.First, we show that GFP-UBE3D is recruited to damage sites by PCNA, through a PCNA-interacting protein (PIP) box. Furthermore, UBE3D interacts with KAP1 via R377R378 and oxidation of the AMD-associated V379M mutation abolishes KAP1-UBE3D binding. By MNase assays, UBE3D depletion reduces the chromatin relaxation levels upon DNA damage. In addition, UBE3D depletion renders less KAP1 recruitment. Compared with wild type, blue light induces less damage in UBE3D+/- mice as measured by ERG and OCT, consistent with our biochemical results.Hence, we propose that one potential mechanism that UBE3D-V379M contributes to AMD pathogenesis might be via defective DNA damage repair linked with oxidative stress and our results offered a potential direction for the treatment of AMD.
第一作者机构：[1]Department of Ophthalmology, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Peking University People's Hospital Beijing, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Ophthalmology, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Peking University People's Hospital Beijing, China.[2]Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing, China.[9]Department of Ophthalmology, Xiamen Eye Center of Xiamen University, Xiamen, China.[*1]Department of Ophthalmology, Eye Diseases and Optometry Institute,Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry,Peking University Health Science Center, Peking University People’s Hospital, Beijing 100044, China[*2]Beijing Key Laboratory of DNA Damage Response, College of Life Sciences, Capital Normal University, Beijing 100048, China[*3]Department of Ophthalmology, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry,Peking University Health Science Center, Peking University People’s Hospital, Beijing 100044, China
推荐引用方式(GB/T 7714)：
Xu Ningda,Liu Yue,Nai Shanshan,et al.UBE3D Is Involved in Blue Light-Induced Retinal Damage by Regulating Double-Strand Break Repair[J].INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE.2022,63(10):doi:10.1167/iovs.63.10.7.
APA：
Xu Ningda,Liu Yue,Nai Shanshan,Tao Yong,Ding Yuehe...&Huang Lvzhen.(2022).UBE3D Is Involved in Blue Light-Induced Retinal Damage by Regulating Double-Strand Break Repair.INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE,63,(10)
MLA：
Xu Ningda,et al."UBE3D Is Involved in Blue Light-Induced Retinal Damage by Regulating Double-Strand Break Repair".INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 63..10(2022)
医学