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      Autophagic UVRAG Promotes UV-induced Photolesion Repair by Activation of the CRL4 DDB2 E3 Ligase

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          SUMMARY

          Ultraviolet (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.

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          E-TOC

          UV-induced DNA damage is a risk factor for skin cancers. Yang et al. demonstrate that UVRAG targets DDB1 and activates the DDB1-containing CRL4 DDB2 ubiquitin-ligase complex, resulting in efficient photolesion repair. Reduced levels of UVRAG correlates with increased UV-signature loads in skin melanoma, which could potentially influence melanoma predisposition and progression.

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          Author and article information

          Journal
          9802571
          20730
          Mol Cell
          Mol. Cell
          Molecular cell
          1097-2765
          1097-4164
          19 April 2016
          19 May 2016
          19 May 2017
          : 62
          : 4
          : 507-519
          Affiliations
          [1 ]Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
          [2 ]Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
          [3 ]Department of Biological Sciences, KAIST Institute for Biocentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
          [4 ]Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA
          [5 ]State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
          Author notes
          Contact information: Chengyu Liang, Department of Molecular Microbiology and Immunology, University of Southern California, Room 5507, MC NRT 9605, 1450 Biggy Street, Los Angeles, CA 90033, chengyu.liang@ 123456med.usc.edu
          Article
          PMC4875571 PMC4875571 4875571 nihpa778847
          10.1016/j.molcel.2016.04.014
          4875571
          27203177
          205c7afd-3263-4737-9065-caeb6663dbf1
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