UV-induced DNA lesion mapping reveals that carcinogen susceptibility is regulated by genome architecture and dictates cancer mutagenesis

In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries in cells at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as a previously unrecognized origin of mutagenesis that is regulated by nuclear architecture and dictates genome instability in cancer. IP of DNA lesions, followed by in-vitro repair and next-generation sequencing

本研究首次构建了紫外线（ultraviolet, UV）辐射诱导的人类全基因组DNA损伤定量图谱。紫外线作为阳光中普遍存在的致癌物质，可引发皮肤癌。值得注意的是，原代细胞全基因组范围内的致癌原易感模式，与恶性黑色素瘤的突变频率显著吻合。令人意外的是，脱氧核糖核酸酶敏感常染色质（DNase-accessible euchromatin）可抵御UV诱导的损伤，而位于核周的核纤层关联异染色质（lamina-associated heterochromatin）则易受UV损伤。诸多癌症驱动基因本身的致癌原易感程度更高，其中在黑色素瘤中突变频率最高的BRAF癌基因便是典型代表。上述研究结果首次在全基因组层面展现了癌变早期阶段细胞内DNA损伤的全貌。此外，本研究还揭示了致癌原易感性是一种此前未被认知的诱变来源，其受核架构调控，并决定了癌症中的基因组不稳定性。本研究采用的实验方法为：对DNA损伤进行免疫沉淀（IP），随后开展体外修复与下一代测序。