Uridine-cytidine kinase 2 potentiates the mutagenic influence of the antiviral β-d-N4-hydroxycytidine.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
11 Dec 2023
11 Dec 2023
Historique:
accepted:
19
10
2023
revised:
11
10
2023
received:
07
06
2023
pubmed:
13
11
2023
medline:
13
11
2023
entrez:
12
11
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37953355
pii: 7416395
doi: 10.1093/nar/gkad1002
pmc: PMC10711452
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
12031-12042Subventions
Organisme : Victorian State Government Operational Infrastructure Support
Organisme : Australian Government NHMRC IRIISS
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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