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Thymidine rescues ATR kinase inhibitor-induced deoxyuridine contamination in genomic DNA, cell death, and interferon-α/β expression
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 f...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9646445/ https://www.ncbi.nlm.nih.gov/pubmed/36130512 http://dx.doi.org/10.1016/j.celrep.2022.111371 |
Sumario: | 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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