Uridine-cytidine kinase 2 potentiates the mutagenic influence of the antiviral β-d-N4-hydroxycytidine
- Author(s)
- Xu, Z; Flensburg, C; Bilardi, RA; Majewski, IJ;
- Details
- Publication Year 2023-11-11,Volume 51,Issue #22,Page 12031-12042
- Journal Title
- Nucleic Acids Research
- Abstract
- Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of bacteria or cell lines with the active form of molnupiravir, β-d-N4-hydroxycytidine (NHC, or EIDD-1931), induces mutations in DNA. Yet these results contrast in vivo genotoxicity studies conducted during registration of the drug. Using a CRISPR screen, we found that inactivating the pyrimidine salvage pathway component uridine-cytidine kinase 2 (Uck2) renders cells more tolerant of NHC. Short-term exposure to NHC increased the mutation rate in a mouse myeloid cell line, with most mutations being T:A to C:G transitions. Inactivating Uck2 impaired the mutagenic activity of NHC, whereas over-expression of Uck2 enhanced mutagenesis. UCK2 is upregulated in many cancers and cell lines. Our results suggest differences in ribonucleoside metabolism contribute to the variable mutagenicity of NHC observed in cancer cell lines and primary tissues.
- Publisher
- Oxford Academic
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 37953355
- Publisher's Version
- https://doi.org/10.1093/nar/gkad1002
- Open Access at Publisher's Site
https://doi.org/10.1093/nar/gkad1002- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-11-20 03:33:01
Last Modified: 2023-12-13 10:19:46