title: Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif.
abstract: CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Poulos
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Julie A I
authors.initials: JAI
authors.lastname: Thoms
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Yi Fang
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2052, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: jason.wong@unsw.edu.au.
authors.forename: Jason W H
authors.initials: JWH
authors.lastname: Wong
mesh_terms: D001665:Binding Sites; D000076246:CCCTC-Binding Factor / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D000097722:Cohesins; C000619697:CTCF protein, human
keywords: COLO-829; CTCF; allele-specific ChIP-seq; cohesin; melanoma; nucleotide excision repair; somatic mutation; topologically associating domain