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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma.

Authors: Sivapragasam, Smitha; Stark, Bastian; Albrecht, Amanda V; Bohm, Kaitlynne A; Mao, Peng; Emehiser, Raymond G; Roberts, Steven A; Hrdlicka, Patrick J; Poon, Gregory M K; Wyrick, John J

Published In EMBO J, (2021 Oct 18)

Abstract: Somatic mutations in DNA-binding sites for CCCTC-binding factor (CTCF) are significantly elevated in many cancers. Prior analysis has suggested that elevated mutation rates at CTCF-binding sites in skin cancers are a consequence of the CTCF-cohesin complex inhibiting repair of UV damage. Here, we show that CTCF binding modulates the formation of UV damage to induce mutation hot spots. Analysis of genome-wide CPD-seq data in UV-irradiated human cells indicates that formation of UV-induced cyclobutane pyrimidine dimers (CPDs) is primarily suppressed by CTCF binding but elevated at specific locations within the CTCF motif. Locations of CPD hot spots in the CTCF-binding motif coincide with mutation hot spots in melanoma. A similar pattern of damage formation is observed at CTCF-binding sites in vitro, indicating that UV damage modulation is a direct consequence of CTCF binding. We show that CTCF interacts with binding sites containing UV damage and inhibits repair by a model repair enzyme in vitro. Structural analysis and molecular dynamic simulations reveal the molecular mechanism for how CTCF binding modulates CPD formation.

PubMed ID: 34487363 Exiting the NIEHS site

MeSH Terms: Binding Sites; Binding, Competitive; CCCTC-Binding Factor/chemistry*; CCCTC-Binding Factor/genetics; CCCTC-Binding Factor/metabolism; Cell Line, Tumor; DNA Damage; DNA Repair*; Gene Expression; Humans; Melanoma/genetics*; Melanoma/metabolism; Melanoma/pathology; Molecular Dynamics Simulation; Mutation; Protein Binding; Protein Serine-Threonine Kinases/chemistry*; Protein Serine-Threonine Kinases/genetics; Protein Serine-Threonine Kinases/metabolism; Pyrimidine Dimers/biosynthesis; Pyrimidine Dimers/chemistry; Pyrimidine Dimers/radiation effects*; Skin Neoplasms/genetics*; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; Ultraviolet Rays

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