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Nucleic Acids Research, 1989, Vol. 17, No. 22 9231-9244
© 1989

MOLECULAR BIOLOGY

Aphidicolin resistance in Herpes simplex virus type I reveals features of the DNA polymerase dNTP binding site

Jennifer D. Hall*, Yisheng Wang, John Pierpont, Mark S. Berlin, Stephen E. Rundlett and Suann Woodward

Department of Molecular and Cellular Biology, University of Arizona Tucson, AZ 85721, USA

*To whom correspondence should be addressed

Received July 20, 1989. Revised October 19, 1989. Accepted October 19, 1989.

We describe the mapping and sequencing of mutations within the DNA polymerase gene of herpes simplex virus type 1 which confer resistance to aphidicolin, a DNA polymerase inhibitor. The mutations occur near two regions which are highly conserved among DNA polymerases related to the herpes simplex enzyme. They also occur near other herpes simplex mutations which affect the interactions between the polymerase and deoxyribonucleoside triphosphate substrates. Consequently, we argue in favor of the idea that the aphidicolin binding site overlaps the substrate binding site and that the near-by conserved regions are functionally required for substrate binding. Our mutants also exhibit abnormal sensitivity to another DNA polymerase inhibitor, phosphonoacetic acid. This drug is thought to bind as an analogue of pyrophosphate. A second-site mutation which suppresses the hypersensitivity of one mutant to phosphonoacetic acid (but not its aphidicolin resistance) is described. This second mutation may represent a new class of mutations, which specifically affects pyrophosphate, but not substrate, binding.


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