 Abstract, XP is a genetic disorder caused by mutations in genes of the nucleotide-excision repair, NER, pathway, groups AG, or in translation synthesis DNA polymerase ETA-V. These mutations lead to an increased skin cancer risk, which can reach thousands of times higher than the general population. In this paper, we analyzed 38 skin cancer genomes from 5 XP groups and found that the activity of NER determines the heterogeneous mutation rates across these genomes. Additionally, our results show that transcription-coupled NER extends beyond the gene boundaries, reducing the intergenic mutation rate. Furthermore, experiments with the PLLH knockout cell line revealed the role of polymerase ETA in the error-free bypass of I, rare TPG and TPA DNA lesions, 2, 3 nucleotides in pyrimidine dimers, and, 3, TPT photodimers. Finally, our study unveils the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population. This article was authored by Andrei Ayyuchinko, Figma Rajabi, Teza Braspetta, and others. We are article.tv, links in the description below.