Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.

暴露在阳光中的紫外线 (UV) 辐射下会造成 DNA 损伤，如果不加以修复，可能会诱发突变并导致皮肤癌。两种最常见的紫外线诱导的 DNA 损伤是顺式环丁烷嘧啶二聚体 (CPD) 和嘧啶 (6-4) 嘧啶酮光产物 (6-4PP)，两者都可以引发突变。有趣的是，许多癌症的基因组突变频率是异质的，异染色质显着增加。与常染色质相比，在异染色质中观察到相应的紫外线损伤敏感性增加和修复减少。然而，CPD 和 6-4PP 对诱变的个体贡献尚未在特定的基因组和表观基因组背景下进行系统研究。在这项研究中，我们比较了原代细胞中 6-4PP 和 CPD 病变丰度的全基因组图谱，并进行了全面分析，以确定与易感性相关的遗传和表观遗传特征。总体而言，我们发现 6-4PP 和 CPD 形成之间高度相似，两者都在异染色质区域中富集。然而，当检查两种 UV 损伤的相对水平时，我们发现二价和 Polycomb 抑制的染色质状态特别容易受到 6-4PP 的影响。有趣的是，当将这些区域的紫外线敏感性和修复与黑色素瘤突变频率进行比较时，观察到不同的模式，即敏感性并不总是与修复和突变频率呈负相关。功能富集分析暗示了这些区域的负选择机制，这些区域对于细胞活力、免疫功能和突变时诱导细胞死亡至关重要。最终，这些结果揭示了导致黑色素瘤的紫外线引起的病变之间的相似性和差异。