ArticleProceedings of the National Academy of Sciences of the United States of America2014
Mechanism of ganciclovir-induced chain termination revealed by resistant viral polymerase mutants with reduced exonuclease activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 51 citations in OpenAlex.
- Host DNA repair factors empower a mechanism of antiviral nucleoside analog resistance.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Development of ganciclovir as an anti-human cytomegalovirus drug: historical perspectives and future prospects.The Journal of general virology · 2026Review
- Host DNA repair factors empower a mechanism of antiviral nucleoside analog resistance.bioRxiv : the preprint server for biology · 2026Article
- Antagonistic co-evolution throughout the herpesvirus life cycle.Virus evolution · 2026Review
- Inhibition of human cytomegalovirus replication by valaciclovir.The Journal of general virology · 2025Article
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- Evolutionary Dynamics of Accelerated Antiviral Resistance Development in Hypermutator Herpesvirus.Molecular biology and evolution · 2024Article
- Suicidal Phenotype of Proofreading-Deficient Herpes Simplex Virus 1 Polymerase Mutants.Journal of virology · 2023Article
- Cytomegalovirus retinitis in the highly active anti-retroviral therapy era.Annals of eye science · 2022Article
- Potential Antiviral Action of Alkaloids.Molecules (Basel, Switzerland) · 2022Review
- Mechanisms of Coronavirus Genome Stability As Potential Targets for Antiviral Drugs.Herald of the Russian Academy of Sciences · 2022Article
- Opposite effects of cytomegalovirus UL54 exonuclease domain mutations on acyclovir and cidofovir susceptibility.Antiviral research · 2021Article
- Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients.Cell stem cell · 2021Article
- Remdesivir for the treatment of Covid-19: the value of biochemical studies.Current opinion in virology · 2021Review
- Human cytomegalovirus-induced host protein citrullination is crucial for viral replication.Nature communications · 2021Article
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- Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.Science advances · 2021Review
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- Boron-containing nucleosides as tools for boron-neutron capture therapy.American journal of cancer research · 2021Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Many antiviral and anticancer drugs are nucleoside analogs that target polymerases and cause DNA chain termination. Interestingly, ganciclovir (GCV), the first line of therapy for human cytomegalovirus (HCMV) infections, induces chain termination despite containing the equivalent of a 3'-hydroxyl group. Certain HCMV GCV resistance (GCV(r)) mutations, including ones associated with treatment failures, result in substitutions in the 3'-5' exonuclease (Exo) domain of the catalytic subunit of the viral DNA polymerase (Pol). To investigate how these mutations confer resistance, we overexpressed and purified wild-type (WT) HCMV Pol and three GCV(r) Exo mutants. Kinetic studies provided little support for resistance being due to effects on Pol binding or incorporation of GCV-triphosphate. The mutants were defective for Exo activity on all primer templates tested, including those with primers terminating with GCV, arguing against the mutations increasing excision of the incorporated drug. However, although the WT enzyme terminated DNA synthesis after incorporation of GCV-triphosphate and an additional nucleotide (N+1), the Exo mutants could efficiently synthesize DNA to the end of such primer templates. Notably, the Exo activity of WT Pol rapidly and efficiently degraded N+2 primer templates to N+1 products that were not further degraded. On N+1 primer templates, WT Pol, much more than the Exo mutants, converted the incoming deoxynucleoside triphosphate to its monophosphate, indicative of rapid addition and removal of incorporated nucleotides ("idling"). These results explain how GCV induces chain termination and elucidate a previously unidentified mechanism of antiviral drug resistance.
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