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

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Somatic mutations at CCCTC-binding factor (CTCF) sites are common in cancers.
• Previous studies linked elevated mutations at CTCF sites in skin cancer to UV damage repair inhibition by the CTCF-cohesin complex.

Purpose of the Study:

• To investigate how CTCF binding influences UV damage formation and mutation patterns.
• To elucidate the molecular mechanisms underlying CTCF's role in UV-induced mutagenesis.

Main Methods:

• Genome-wide CPD-seq analysis in UV-irradiated human cells.
• In vitro studies of UV damage formation at CTCF-binding sites.
• Biochemical assays with a model DNA repair enzyme.
• Structural analysis and molecular dynamic simulations.

Main Results:

• CTCF binding suppresses UV-induced cyclobutane pyrimidine dimer (CPD) formation overall.
• CPD formation is elevated at specific locations within the CTCF motif.
• These CPD hotspots correlate with mutation hotspots observed in melanoma.
• CTCF directly interacts with UV-damaged DNA and inhibits in vitro repair.

Conclusions:

• CTCF binding actively modulates UV damage formation, creating mutation hotspots.
• This modulation is a direct consequence of CTCF binding to DNA.
• The findings reveal a novel molecular mechanism for UV-induced mutagenesis at CTCF sites.