Uridine-cytidine kinase 2 pot entiat es the mutagenic influence of the antiviral β-d-N4-hydroxycytidine
Zhen Xu, Chr Istoff Er Flensburg, Rebecca A Bilardi, Ian J Majewski
doi:10.1093/nar/gkad1002/7416395
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, w e f ound that inactiv ating the p yrimidine salv age pathw a y component uridine-cytidine kinase 2 ( Uck2 ) renders cells more tolerant of NHC. Short-term exposure to NHC increased the mutation rate in a mouse m y eloid cell line, with most mutations being T:A to C:G transitions. Inactivating Uck2 impaired the mutagenic activity of NHC, whereas o v er-e xpression of Uck2 enhanced mutagenesis. UCK2 is upregulated in many cancers and cell lines. Our results suggest differences in ribonucleoside metabolism contribute to the variable mut agenicit y of NHC observed in cancer cell lines and primary tissues.
Supplementary data Supplementary Data are available at NAR Online.
A c kno wledg ements We would like to thank our colleagues for useful discussions during preparation of the manuscript. The manuscript made use of data from The Genotype-Tissue Expression (GTEx) Project. GTEx was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were first obtained from the GTEx Portal on 24 March 2023 then updated on 22 August 2023. Figure 1
Conflict of interest statement None declared.
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