Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase

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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.
Publisher
CELL PRESS
Issue Date
2016-05
Language
English
Article Type
Article
Keywords

NUCLEOTIDE EXCISION-REPAIR; DNA-DAMAGE; INDUCED UBIQUITYLATION; CUTANEOUS MELANOMA; PROTEIN; COMPLEX; XPC; MUTATIONS; CANCER; RISK

Citation

MOLECULAR CELL, v.62, no.4, pp.507 - 519

ISSN
1097-2765
DOI
10.1016/j.molcel.2016.04.014
URI
http://hdl.handle.net/10203/209519
Appears in Collection
BS-Journal Papers(저널논문)
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