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CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma
The EMBO Journal  (IF11.598),  Pub Date : 2021-09-06, DOI: 10.15252/embj.2021107795
Smitha Sivapragasam, Bastian Stark, Amanda V Albrecht, Kaitlynne A Bohm, Peng Mao, Raymond G Emehiser, Steven A Roberts, Patrick J Hrdlicka, Gregory M K Poon, John J Wyrick

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.