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July 4th, 2025
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The University of North Carolina at Chapel Hill
cancer biology
biorxiv

DIFFERENTIAL ROLES OF RAD18 IN REPRESSING CARCINOGEN- AND ONCOGENE-DRIVEN MUTAGENESIS IN VIVO

Anand, J.Open in Google Scholar•Brown, B. W.Open in Google Scholar•Lou, J.Open in Google Scholar•Gu, Q.Open in Google Scholar•Yang, Y.Open in Google Scholar•Droby, G. N.Open in Google Scholar•Wu, D.Open in Google Scholar•Jena, A.Open in Google Scholar•Xie, J.Open in Google Scholar•Fedoriw, Y.Open in Google Scholaret al.

The DNA repair protein RAD18 activates Y-family Trans-Lesion Synthesis (TLS) DNA polymerases that are DNA damage-tolerant and potentially error-prone. RAD18 is also frequently overexpressed and pathologically activated in cancer cells. However, the extent to which RAD18 shapes cancer genomes and impacts tumorigenesis is unclear. Therefore, we tested the effect of Rad18 status on chemically-induced and oncogene-driven tumorigenesis. In a chemically-induced oral carcinogenesis model, acute (2-16 days) 4NQO-treatment induces expression of Rad18 and TLS polymerase mRNAs in mouse oral epithelial cells prior to emergence of oral squamous cell carcinomas (OSCCs). Chronic (8 week) 4NQO-treatment leads to onset of oral tumors that is accelerated in Rad18-/- mice when compared with Rad18+/+ animals. Analysis of OSCC genomes reveals increased levels of G(C)>T(A) transversions in Rad18-/- tumors when compared with Rad18+/+. Therefore, Rad18 promotes error-free bypass of 4NQO-induced DNA lesions and suppresses 4NQO-induced oral carcinogenesis. In a KrasG12D-induced lung carcinogenesis model, Rad18-deficiency did not affect rates or incidence of oncogene-induced lung tumors or mutations. Taken together, we demonstrate that Rad18 has context-specific tumor-suppressive activity. Given the prevalence of 4NQO-like environmental exposures, RAD18 is highly likely to shape human cancer genomes and perhaps influence other aspects of the tumorigenic process.

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