Drug‐Resistant Mutants of Herpes Simplex Virus Type 2 with a Mutator or Antimutator Phenotype

Nishiyama, Yukihiro; Yoshida, Shonen; Tsurumi, Tatsuya; Yamamoto, Naohiko; Maeno, Kazuo

doi:10.1111/j.1348-0421.1985.tb00837.x

Cited by 9 publications

(8 citation statements)

References 16 publications

(11 reference statements)

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“…Furthermore, the A498V and A498T mutations exhibited, respectively, moderate and acute hypersensitivity to PAA or 9-β-D-arabinofuranosyladenine (AraA), and moderate hypersensitivity to 1-β-D-arabinofuranosylcytosine (AraC). While it is interesting that resistance to a dCTP competitor, aphidicolin, conferred increased sensitivity to, and thus likely altered affinity for, the nucleotide analogues AraA and AraC, previous studies in Herpes simplex virus and other systems have reported similar trends (Gibbs et al, 1988; Hall et al, 1989; Matsumoto et al, 1990; Nishiyama et al, 1985). Similarly, this inverse relationship between aphidicolin and PAA / nucleoside analogue resistance and sensitivity appears to hold true for the three aforementioned mutations conferring PAA resistance: C356T, G372D, G380S.…”

Section: : the Dna Polymerase: Genetic Dissectionmentioning

confidence: 84%

The vaccinia virus DNA polymerase and its processivity factor

Czarnecki

Traktman

2017

Virus Research

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Vaccinia virus is the prototypic poxvirus. The 192 kilobase double-stranded DNA viral genome encodes most if not all of the viral replication machinery. The vaccinia virus DNA polymerase is encoded by the E9L gene. Sequence analysis indicates that E9 is a member of the B family of replicative polymerases. The enzyme has both polymerase and 3′–5′ exonuclease activities, both of which are essential to support viral replication. Genetic analysis of E9 has identified residues and motifs whose alteration can confer temperature-sensitivity, drug resistance (phosphonoacetic acid, aphidicolin, cytosine arabinsode, cidofovir) or altered fidelity. The polymerase is involved both in DNA replication and in recombination. Although inherently distributive, E9 gains processivity by interacting in a 1:1 stoichiometry with a heterodimer of the A20 and D4 proteins. A20 binds to both E9 and D4 and serves as a bridge within the holoenzyme. The A20/D4 heterodimer has been purified and can confer processivity on purified E9. The interaction of A20 with D4 is mediated by the N′-terminus of A20. The D4 protein is an enzymatically active uracil DNA glycosylase. The DNA-scanning activity of D4 is proposed to keep the holoenzyme tethered to the DNA template but allow polymerase translocation. The crystal structure of D4, alone and in complex with A201–50 and/or DNA has been solved. Screens for low molecular weight compounds that interrupt the A201–50/D4 interface have yielded hits that disrupt processive DNA synthesis in vitro and/or inhibit plaque formation. The observation that an active DNA repair enzyme is an integral part of the holoenzyme suggests that DNA replication and repair may be coupled.

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Section: : the Dna Polymerase: Genetic Dissectionmentioning

confidence: 84%

The vaccinia virus DNA polymerase and its processivity factor

Czarnecki

Traktman

2017

Virus Research

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“…; cells were harvested at 3 or 4 days p.i. sometimes associated with altered polymerase fidelity (17,18,20,28,32). In this context, the Aphr isolates were investigated for alterations in mutation rate by assaying the spontaneous frequency of viral mutants resistant to PAA, IBT, and rifampin.…”

Section: Dose-dependent Inhibition Of Vaccinia Virus Replication Bymentioning

confidence: 99%

Genetic characterization of the vaccinia virus DNA polymerase: identification of point mutations conferring altered drug sensitivities and reduced fidelity

Taddie

Traktman

1991

J Virol

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We determined that 85 ,iM aphidicolin was sufficient to block macroscopic plaque formation by vaccinia virus and to cause a 104-fold reduction in viral yield from a wild-type infection. A chemically mutagenized viral stock was passaged sequentially in the presence of drug, and plaque-purified viral stocks resistant to aphidicolin were isolated and characterized. By use of a marker rescue protocol, the lesion in each mutant was found to map within the same 500-bp fragment within the DNA polymerase gene. All of the mutants were found to contain a single nucleotide change in the same codon. In nine of these mutants, the alanine residue at position 498 was changed to a threonine, whereas a 10th mutant sustained a valine substitution at this position. Congenic viral strains which carried the Aphr lesion in an unmutagenized wild-type background were isolated. The Thr and Val mutations were found to confer equivalent levels of drug resistance. In the presence of drug, viral yields were 25% of control levels, and the levels of viral DNA synthesized were 30 to 50% of those seen in control infections. The two mutations also conferred an equivalent hypersensitivity to the cytosine analog

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“…Viral DNA polymerases from wild type herpes simplex virus type 2 (HSV-2) and from virus resistant to phosphonoacetic acid (PAAr) or to aphidicolin (Aphr) were purified from infected cells, as described by Nishiyama et al (9), as have the mutator (Aphr) and antimutator (PAAr) viral phenotypes (10).…”

Section: Enzymesmentioning

confidence: 99%

On the fidelity of DNA replication: herpes DNA potymerase and its associated exonuclease

Abbotts¹,

Nishiyama²,

Yoshida³

et al. 1987

Nucl Acids Res

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Procaryotic DNA polymerases contain an associated 3'----5' exonuclease activity which provides a proofreading function and contributes substantially to replication fidelity. DNA polymerases of the eucaryotic herpes-type viruses contain similar associated exonuclease activities. We have investigated the fidelity of polymerases purified from wild type herpes simplex virus, as well as from mutator and antimutator strains. On synthetic templates, the herpes enzymes show greater relative exonuclease activities, and greater ability to excise a terminal mismatched base, than procaryotic DNA polymerases which proofread. On a phi X174 natural DNA template, the herpes enzymes are more accurate than purified eucaryotic DNA polymerases; the error rate is similar to E. coli polymerase I. However, conditions which abnegate proofreading by E. coli polymerase I have little effect on the herpes enzymes. We conclude that either these viral polymerases are accurate in the absence of proofreading, or the conditions examined have little effect on proofreading by the herpes DNA polymerases.

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Drug‐Resistant Mutants of Herpes Simplex Virus Type 2 with a Mutator or Antimutator Phenotype

Cited by 9 publications

References 16 publications

The vaccinia virus DNA polymerase and its processivity factor

The vaccinia virus DNA polymerase and its processivity factor

Genetic characterization of the vaccinia virus DNA polymerase: identification of point mutations conferring altered drug sensitivities and reduced fidelity

On the fidelity of DNA replication: herpes DNA potymerase and its associated exonuclease

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