Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumors in vivo

The E3 ubiquitin ligase Rad18 promotes a damage-tolerant and error-prone mode of DNA replication termed trans-lesion synthesis that is pathologically activated in cancer. However, the impact of vertebrate on cancer genomes is not known. To determine how Rad18 affects mutagenesis , we have developed and implemented a novel computational pipeline to analyze genomes of carcinogen (7, 12-Dimethylbenz[a]anthracene, DMBA)-induced skin tumors from and mice. We show that mediates specific mutational signatures characterized by high levels of A(T)>T(A) single nucleotide variations (SNVs). In tumors, an alternative mutation pattern arises, which is characterized by increased numbers of deletions >4 bp. Comparison with annotated human mutational signatures shows that COSMIC signature 22 predominates in tumors whereas tumors are characterized by increased contribution of COSMIC signature 3 (a hallmark of BRCA-mutant tumors). Analysis of The Cancer Genome Atlas shows that expression is strongly associated with high SNV burdens, suggesting RAD18 also promotes mutagenesis in human cancers. Taken together, our results show Rad18 promotes mutagenesis , modulates DNA repair pathway choice in neoplastic cells, and mediates specific mutational signatures that are present in human tumors.