Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4DDB2 E3 Ligase

• Published in: Molecular cell 2016-05, Vol.62 (4), p.507-519
• Main Authors: Yang, Yongfei, He, Shanshan, Wang, Qiaoxiu, Li, Fan, Kwak, Mi-Jeong, Chen, Sally, O’Connell, Douglas, Zhang, Tian, Pirooz, Sara Dolatshahi, Jeon, YongHeui, Chimge, Nyam-Osor, Frenkel, Baruch, Choi, Younho, Aldrovandi, Grace M., Oh, Byung-Ha, Yuan, Zengqiang, Liang, Chengyu
• Format: Article
• Language: English
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.04.014

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 (CRL4DDB2) 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 CRL4DDB2-mediated NER and suggest that its expression levels may influence melanoma predisposition. [Display omitted] •UVRAG is strictly required for global genomic NER, independently of autophagy•UVRAG accumulates at photolesions and associates with DDB1•UVRAG expression inversely correlates with UV-like mutagenesis in melanoma•UVRAG-DDB1 interaction antagonizes CAND1 and activates CRL4DDB2 E3 ligase complex UV-induced DNA damage is a risk factor for skin cancers. Yang et al. demonstrate that UVRAG targets DDB1 and activates the DDB1-containing CRL4DDB2 ubiquitin ligase complex, resulting in efficient photolesion repair. Reduced levels of UVRAG correlate with increased UV-signature loads in skin melanoma, which could potentially influence melanoma predisposition and progression.