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Related functional domains in virus DNA polymerases
The EMBO Journal
|January 1, 1987
Summary
Drug resistance in herpes simplex virus DNA polymerase mutants primarily involves conserved amino acid substitutions. These findings identify key functional domains and explain challenges in developing acyclovir-resistant therapies.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Herpes simplex virus (HSV) DNA polymerase is a target for antiviral drugs like acyclovir (ACV).
- Drug resistance can arise from mutations in the viral DNA polymerase.
- Understanding these mutations is crucial for developing effective antiviral therapies.
Purpose of the Study:
- To analyze drug-resistant mutations in HSV DNA polymerase.
- To identify conserved domains within herpesvirus DNA polymerases.
- To compare these domains with those in other viral DNA polymerases.
Main Methods:
- Analysis of drug-resistant DNA polymerase mutants of herpes simplex virus.
- Comparative sequence analysis of DNA polymerases from human herpesviruses, adenovirus type 2, vaccinia virus, and phage phi 29.
Main Results:
- Most drug resistance lesions (5/6) are substitutions at amino acid residues conserved across all four human herpesviruses.
- These lesions cluster in regions of high residue conservation within the polypeptide.
- Homologous domains (regions I-III) were identified in adenovirus, vaccinia, and phage phi 29 DNA polymerases, with similar spatial distribution.
Conclusions:
- Identified conserved domains likely play critical functional roles in viral DNA polymerase activity.
- The limited sites for drug resistance mutations may explain the difficulty in selecting acyclovir-resistant mutants in vitro and in vivo.
- Conserved domains in herpesvirus DNA polymerases are also present in other viral DNA polymerases, suggesting shared functional importance.