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UL52 Primase Interactions in the Herpes Simplex Virus 1 Helicase-Primase Are Affected by Antiviral Compounds and Mutations Causing Drug Resistance

Journal article
Authors Isabella Muylaert
Zhiyuan Zhao
Per Elias
Published in Journal of Biological Chemistry
Volume 289
Issue 47
ISSN 0021-9258
Publication year 2014
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Links dx.doi.org/10.1074/jbc.M114.609453
Keywords ORIGIN-BINDING PROTEIN, DNA-SYNTHESIS, GENE-PRODUCTS, UL8 PROTEIN, ACYCLOVIR, POLYMERASE, MECHANISM, COMPLEX, REPLICATION, SUPERFAMILY, Biochemistry & Molecular Biology, OW ND, 1993, VIROLOGY, V196, P413
Subject categories Clinical Medicine

Abstract

Herpes simplex virus 1 (HSV-1) UL5/8/52 helicase-primase complex is required for DNA unwinding at the replication fork and synthesis of primers during virus replication, and it has become a promising novel target for antiviral therapy. Using molecular cloning, we have identified three separate domains of UL52. Co-immunoprecipitation experiments in extracts from cells transiently expressing HA-tagged UL5, FLAG-UL8, and enhanced GFP-tagged UL52 domains revealed that the N-terminal domain of UL52 primase binds UL5 helicase and the middle domain interacts with the UL8 accessory protein. In addition, an interaction between the single strand DNA-binding protein ICP8 and the UL52 middle domain was observed. The complex between UL5 and UL52 was stabilized by the antiviral compound BAY 54-6322, and mutations providing resistance to the drug obliterate this effect. Our results also suggest a mechanism for accommodating conformational strain resulting from movement of UL5 and UL52 in opposite directions on the lagging strand template, and they identify molecular complexes that can be further examined by structural biology techniques to resolve the mechanism of primer synthesis during herpesvirus replication. Finally, they help to explain the mechanism of action of a novel class of antiviral compounds currently being evaluated in clinical trials.

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