Genomic profiles of ultraviolet-induced 6-4PP susceptibilities and potential new roles in melanoma development

In this study we generated a genome map of 6-4PP lesion abundance in primary cells and conducted a comprehensive analysis to determine the epigenetic and genomic factors regulating 6-4PP susceptibility across the genome. We found that 6-4PP distribution across the genome is very similar to CPD, highest in heterochromatin regions near the nuclear periphery. Interestingly, we identified regions more susceptible to 6-4PP, but not CPD, located in bivalent and polycomb repressed chromatin states found closer to the center of the nucleus. Genes and enhancers in regions with the highest 6-4PP susceptibility are more mutated and have lower repair activity. However, these differences were not observed for genes located in regions more susceptible to 6-4PP and not CPD. Functional analysis of genes in these regions are involved in essential cellular processes required for cell growth and proteins localized to the cell membrane. This study reveals new insights into the genomic factors regulating 6-4PP susceptibility and suggest a novel role for 6-4PP lesions in skin cancer development. IP of 6-4PP lesions, followed by in-vitro repair and next-generation sequencing.