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. Overall design: IP of DNA lesions, followed by in-vitro repair and next-generation sequencing