title: Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair.
abstract: UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non-transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non-transcribed and silent regions of the genome. This study aimed to examine the relationship between UVB and GGR in melanoma. DNA repair capacity and relative expression of NER in melanocytes and melanoma cell lines before and after treatment with UVB was quantified. Transcript expression from 196 melanomas was compared to clinical parameters including solar elastosis and whole transcriptome data collected. Melanoma cell lines showed significantly reduced DNA repair when compared to melanocytes, most significantly in the S phase of the cell cycle. Expression of GGR components XPC, DDB1 and DDB2 was significantly lower in melanoma after UVB. In the melanoma tumours, XPC expression correlated with age of diagnosis and low XPC conferred significantly poorer survival. The same trend was seen in the TCGA melanoma dataset. Reduced GGR in melanoma may contribute to the UV mutation spectrum of the melanoma genome and adds further to the growing evidence of the link between UV, NER and melanoma.
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Budden
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Davey
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.|Melanoma Institute of Australia, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, Sydney, NSW, Australia.|Hunter Area Pathology Service, Pathology North, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Vilain
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Ashton
authors.affiliation: Hunter Area Pathology Service, Pathology North, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Braye
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Beveridge
authors.affiliation: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Nikola A
authors.initials: NA
authors.lastname: Bowden
mesh_terms: D000367:Age Factors; D001706:Biopsy; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008027:Light; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C086984:XPC protein, human
keywords: UVB; XPC; global genome repair; melanoma; nucleotide excision repair