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Uridine–cytidine kinase 2 potentiates the mutagenic influence of the antiviral β-d-N4-hydroxycytidine

Xu et al., Nucleic Acids Research, doi:10.1093/nar/gkad1002
Nov 2023  
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In Vitro study showing that molnupiravir increased mutation rates in mouse blood cancer cell lines. The mutagenic effects were enhanced by overexpression of the enzyme uridine-cytidine kinase 2 (Uck2), and lessened in Uck2 knockout cells. The authors suggest variable expression of Uck2 may explain differing results regarding molnupiravir mutagenicity in past studies.
The results suggest that molnupiravir treatment could potentially increase mutation rates in existing cancers that have high expression of Uck2. Increased mutagenesis in tumor cells may enable cancers to become more aggressive, resistant to therapy, or prone to relapse.
Uck2 expression varies significantly across different tissues and situations. Studies have shown that Uck2 is upregulated in diverse cancer types, including lung, breast, liver, bladder, and colorectal cancers. Uck2 expression is higher in actively proliferating tissues like bone marrow, thymus, testes, and fetal liver compared to quiescent tissues; and increases during myeloid and erythroid differentiation of hematopoietic stem cells. Some in vitro data indicates Uck2 may be induced by stress, inflammation, and hypoxia. Viral infection may also alter Uck2 levels.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zhou, Zibat. Multiple analyses have identified variants potentially created by molnupiravir Fountain-Jones, Kosakovsky Pond, Sanderson,
Xu et al., 11 Nov 2023, peer-reviewed, 4 authors.
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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
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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