Key result
HSV-1 D368A mutation severely inhibits viral DNA synthesis and polymerase expression, explaining its lethal phenotype.
The lethal phenotype of the HSV-1 D368A mutation is largely explained by severely reduced polymerase expression rather than the loss of exonuclease activity alone.
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D368A effects in HSV-1 polymerase distinguish expression from exonuclease roles; leaves open validation for antiviral targeting.
Herpesviruses, including herpes simplex virus-1, encode and express a DNA polymerase that is required for replication of their dsDNA genomes. The catalytic subunit of this enzyme contains a 3'-5' exonuclease that is involved in proofreading during replication. Although certain mutations that severely impair exonuclease activity are not lethal to the virus, it was reported that virus containing the substitution of alanine for aspartate 368 (D368A), which ablates exonuclease activity, could not be recovered, raising the possibility that this activity is essential for viral replication. To investigate this issue, we produced virus containing this mutation (D368A Pol) using a complementing cell line. D368A Pol virus was unable to form plaques on non-complementing cells. Viral DNA synthesis and polymerase activity were severely inhibited in D368A-infected cells, as was expression of the enzyme, suggesting that effects on polymerase expression rather than on exonuclease activity per se largely explain the lethal phenotype of this mutation.
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Lawler et al. (2018) studied Herpes simplex virus-1. D368A mutation in HSV-1 DNA polymerase was evaluated on Viral DNA synthesis and polymerase expression. The D368A mutation in HSV-1 DNA polymerase severely inhibited viral DNA synthesis and polymerase expression, explaining the lethal phenotype of this mutation.
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