title: Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.
abstract: UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Qiaoxiu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, KAIST Institute for Biocentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kwak
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: O'Connell
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sara Dolatshahi
authors.initials: SD
authors.lastname: Pirooz
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yong Heui
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Nyam-Osor
authors.initials: NO
authors.lastname: Chimge
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Younho
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Aldrovandi
authors.affiliation: Department of Biological Sciences, KAIST Institute for Biocentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Byung-Ha
authors.initials: BH
authors.lastname: Oh
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: chengyu.liang@med.usc.edu.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000528:radiation effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000528:radiation effects; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059748:Proteolysis; D034622:RNA Interference; D012160:Retina / Q000201:enzymology / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014466:Ultraviolet Rays; D053722:Receptors, Interleukin-17
chemical_list: D002352:Carrier Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C114234:CUL4A protein, human; C491940:Cul4a protein, mouse; C091435:DDB1 protein, human; C117669:DDB2 protein, human; C490415:Ddb1 protein, mouse; C496850:Ddb2 protein, mouse; C557617:GAL4 protein, Drosophila; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C479529:RBX1 protein, human; C540494:RBX1 protein, mouse; C561319:UVRAG protein, Drosophila; C408122:UVRAG protein, human; C512859:UVRAG protein, mouse