In this study, we generated a human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation in retinoblastoma knockout (RB1 KO) cells. Interestingly, we observed increased carcinogen susceptibility in closed HI-C domainS, pericentric and subtelomeric regions in RB1 KO. We also observed increased susceptibility at cancer driver loci such as TERT and TPTE. These loci are highly mutated in melanoma. Finally, we proposed that loss of tumor suppressor function can alter carcinogen susceptibility, and subsequently the mutation frequency of the genome. Overall design: IP of CPD lesions, followed by in-vitro repair and next-generation sequencing