Thymidine rescues ATR kinase inhibition induced deoxyuridine contamination in genomic DNA, cell death, and Type 1 interferon expression
Sugitani, N.; Vendetti, F. P.; Cipriano, A. J.; Pandya, P.; Deppas, J. J.; Moiseeva, T. N.; Schamus-Haynes, S.; Wang, Y.; Palmer, D.; Osmanbeyoglu, H. U.; Bostwick, A.; Snyder, N. W.; Gong, Y.-N.; Aird, K. M.; Delgoffe, G. M.; Beumer, J. H.; Bakkenist, C. J.
Show abstract
ATR kinase is a central regulator of the DNA damage response (DDR) and cell cycle checkpoints. ATR kinase inhibitors (ATRis) combine with radiation to generate CD8+ T cell-dependent responses in mouse models of cancer. We show that ATRis induce CDK1-dependent origin firing across active replicons in CD8+ T cells activated ex vivo while simultaneously decreasing the activity of rate-limiting enzymes for nucleotide biosynthesis. These pleiotropic effects of ATRi induce deoxyuridine (dU) contamination in genomic DNA, R loops, RNA-DNA polymerase collisions, and type-1 interferons (IFN-1). Remarkably, thymidine rescues ATRi-induced dU contamination, cell death, and IFN-1 expression in proliferating CD8+ T cells. Thymidine also rescues ATRi-induced cancer cell death. We propose that ATRi-induced dU contamination contributes to dose-limiting leukocytopenia and inflammation in the clinic and CD8+ T cell dependent anti-tumor responses in mouse models. We conclude that ATR is essential to limit dU contamination in genomic DNA and IFN-1 expression.
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