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Thymidine rescues ATR kinase inhibitor-induced deoxyuridine contamination in genomic DNA, cell death, and interferon-α/β expression
Sugitani, Norie Vendetti, Frank P. Cipriano, Andrew J. Pandya, Pinakin Deppas, Joshua J. Moiseeva, Tatiana N. Schamus-Haynes, Sandra Wang, Yiyang Palmer, Drake Osmanbeyoglu, Hatice U.
Sugitani, Norie
Vendetti, Frank P.
Cipriano, Andrew J.
Pandya, Pinakin
Deppas, Joshua J.
Moiseeva, Tatiana N.
Schamus-Haynes, Sandra
Wang, Yiyang
Palmer, Drake
Osmanbeyoglu, Hatice U.
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Journal article
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2022-09-20
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Cardiovascular Sciences
Cancer and Cellular Biology
Cancer and Cellular Biology
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http://dx.doi.org/10.1016/j.celrep.2022.111371
Abstract
ATR kinase is a central regulator of the DNA damage response (DDR) and cell cycle checkpoints. ATR kinase inhibitors (ATRi's) combine with radiation to generate CD8+ T cell-dependent responses in mouse models of cancer. We show that ATRi's induce cyclin-dependent kinase 1 (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 interferon-α/β (IFN-α/β). Remarkably, thymidine rescues ATRi-induced dU contamination and partially rescues death and IFN-α/β expression in proliferating CD8+ T cells. Thymidine also partially 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-α/β expression.
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Citation
Norie Sugitani, Frank P. Vendetti, Andrew J. Cipriano, Pinakin Pandya, Joshua J. Deppas, Tatiana N. Moiseeva, Sandra Schamus-Haynes, Yiyang Wang, Drake Palmer, Hatice U. Osmanbeyoglu, Anna Bostwick, Nathaniel W. Snyder, Yi-Nan Gong, Katherine M. Aird, Greg M. Delgoffe, Jan H. Beumer, Christopher J. Bakkenist, Thymidine rescues ATR kinase inhibitor-induced deoxyuridine contamination in genomic DNA, cell death, and interferon-α/β expression, Cell Reports, Volume 40, Issue 12, 2022, 111371, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2022.111371.
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Elsevier
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Cell Reports, Vol. 40, Iss. 12
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