Cryptochrome deletion in p53 mutant mice enhances apoptotic and anti-tumorigenic responses to UV damage at the transcriptome level

Abstract

Previous studies have demonstrated that deletion of cryptochrome (Cry) genes protects p53^−/− mutant mice from the early onset of cancer and extends their median life-span by about 1.5-fold. Subsequent in vitro studies had revealed that deletion of Crys enhances apoptosis in response to UV damage through activation of p73 and inactivation of GSK3β. However, it was not known at the transcriptome-wide level how deletion of Crys delays the onset of cancer in p53^−/− mutant mice. In this study, the RNA-seq approach was taken to uncover the differentially expressed genes (DEGs) and pathways following UV-induced DNA damage in p53^−/− and p53^−/−Cry1^−/−Cry2^−/− mouse skin fibroblasts. Gene set enrichment analysis with the DEGs demonstrated enrichment in immune surveillance-associated genes regulated by IFN-γ and genes involved in TNFα signaling via NF-κB. Furthermore, protein network analysis enabled identification of DEGs p21, Sirt1, and Jun as key players, along with their interacting partners. It was also observed that the DEGs contained a high ratio of non-coding transcripts. Collectively, the present study suggests new genes in NF-κB regulation and IFN-γ response, as well as non-coding RNAs, may contribute to delaying the onset of cancer in p53^−/−Cry1^−/−Cry2^−/− mice and increasing the life-span of these animals compared to p53^−/− mice.