Mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene can confer altered drug sensitivities.
Two herpes simplex virus mutants containing mutated residues within the conserved Exo III motif of the polymerase gene were previously shown to be defective in 3'-5' exonuclease activity and exhibited extremely high mutation frequencies. In this study, we have shown that these mutants also exhibited higher resistance to phosphonoacetic acid and sensitivity to aphidicolin and all nucleoside analogs tested, including acyclovir and gangciclovir, compared to wild-type virus. Marker transfer experiments and sequencing analyses demonstrated that these altered phenotypes were the result of mutations within the Exo III motif. The data indicate that, aside from leading to exonuclease deficiency, mutations in the Exo III motif may also affect interaction of nucleoside triphosphates with the catalytic sites of polymerase activity.
Hwang
Y T
YT
Department of Microbiology, and Immunology, College of Medicine, State University of New York, Syracuse 13210, USA. hwangc@vax.cs.hscsyr.edu
Smith
J F
JF
Gao
L
L
Hwang
C B
CB
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology*; D001665:Binding Sites; D002522:Chlorocebus aethiops; D004279:DNA, Viral; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000502:physiology; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043211:Exodeoxyribonuclease V; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000502:physiology; D005814:Genes, Viral; D015751:Genes, pol; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006639:Histidine / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009705:Nucleosides / Q000494:pharmacology*; D016366:Open Reading Frames; D010746:Phosphonoacetic Acid / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011995:Recombination, Genetic; D014443:Tyrosine / Q000235:genetics; D014709:Vero Cells; D014764:Viral Proteins
D000998:Antiviral Agents; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D009705:Nucleosides; D014764:Viral Proteins; D016590:Aphidicolin; D014443:Tyrosine; D006639:Histidine; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; D043211:Exodeoxyribonuclease V; D010746:Phosphonoacetic Acid