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

Jitong Lou; Yang Yang; Qisheng Gu; Brandon A Price; Yuheng Qiu; Yuri Fedoriw; Siddhi Desai; Lisle E Mose; Brian Chen; Satoshi Tateishi; Joel S Parker; Cyrus Vaziri; Di Wu

doi:10.1093/narcan/zcaa037

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

NAR Cancer. 2021 Mar;3(1):zcaa037. doi: 10.1093/narcan/zcaa037. Epub 2021 Jan 6.

Authors

Jitong Lou¹, Yang Yang², Qisheng Gu³, Brandon A Price⁴, Yuheng Qiu⁵, Yuri Fedoriw², Siddhi Desai², Lisle E Mose⁴, Brian Chen¹, Satoshi Tateishi⁶, Joel S Parker⁴, Cyrus Vaziri², Di Wu¹

Affiliations

¹ Department of Biostatistics, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3101 McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA.
² Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 614 Brinkhous-Bullitt Building, Chapel Hill, NC 27599, USA.
³ Division of Oral and Craniofacial Health Sciences, Adam School of Dentistry, University of North Carolina at Chapel Hill, 385 S. Columbia Street, Chapel Hill, NC 27599, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA.
⁵ Department of Statistics, Purdue University, 250 N. University St, West Lafayette, IN 47907, USA.
⁶ Department of Cell Maintenance, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo Chuoku, Kumamoto 860-0811, Japan.

Abstract

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 Rad18 on cancer genomes is not known. To determine how Rad18 affects mutagenesis in vivo, we have developed and implemented a novel computational pipeline to analyze genomes of carcinogen (7, 12-Dimethylbenz[a]anthracene, DMBA)-induced skin tumors from Rad18^+/+ and Rad18^- ^/ ^- mice. We show that Rad18 mediates specific mutational signatures characterized by high levels of A(T)>T(A) single nucleotide variations (SNVs). In Rad18^- ^/- 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 Rad18^+/+ tumors whereas Rad18^- ^/ ^- tumors are characterized by increased contribution of COSMIC signature 3 (a hallmark of BRCA-mutant tumors). Analysis of The Cancer Genome Atlas shows that RAD18 expression is strongly associated with high SNV burdens, suggesting RAD18 also promotes mutagenesis in human cancers. Taken together, our results show Rad18 promotes mutagenesis in vivo, modulates DNA repair pathway choice in neoplastic cells, and mediates specific mutational signatures that are present in human tumors.

Grants and funding

R01 CA215347/CA/NCI NIH HHS/United States