Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Rebecca C. Poulos, Julie A.I. Thoms, Yi Fang Guan, Ashwin Unnikrishnan, John E. Pimanda, Jason W.H. Wong
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.

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Teaser

Poulos et al. identify a specific mutation pattern within CTCF binding sites in skin cancers, which is attributable to differential nucleotide excision repair across the motif. Mutations on highly conserved bases cause allele-specific reduction of CTCF binding. Despite the frequency of these mutations, they are generally under neutral selection in melanoma.


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