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.
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.