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J. Biol. Chem., Vol. 276, Issue 9, 6605-6615, March 2, 2001
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From the Department of Microbiology, University of Connecticut
Health Center, Farmington, Connecticut 06030
UL9, an essential gene for
herpes simplex virus type 1 (HSV-1) DNA replication, exhibits helicase
and origin DNA binding activities. It has been hypothesized that UL9
binds and unwinds the HSV-1 origin of replication, creating a
replication bubble and promoting the assembly of the viral replication
machinery; however, direct confirmation of this hypothesis has not been
possible. Based on the presence of conserved helicase motifs, UL9 has
been classified as a superfamily II helicase. Mutations in conserved
residues of the helicase motifs I
Residues within the Conserved Helicase Motifs of UL9, the
Origin-binding Protein of Herpes Simplex Virus-1, Are Essential for
Helicase Activity but Not for Dimerization or Origin Binding
Activity*
VI of UL9 have been
isolated, and most of them fail to complement a UL9 null
virus in vivo (Martinez R., Shao L., and Weller S. (1992)
J. Virol. 66, 6735-6746). In addition, mutants in
motifs I, II, and VI were found to be transdominant (Malik, A. K.,
and Weller, S. K. (1996) J. Virol. 70, 7859-7866). Here we present the characterization of the biochemical
properties of the UL9 helicase motif mutants. We report
that mutations in motifs I-IV and VI affect the ATPase activity, and
all but the motif III mutation completely abolish the helicase
activity. In addition, mutations in these motifs do not interfere with
UL9 dimerization or the ability of UL9 to bind the HSV-1 origin of replication. Based on the similarity of the helicase motif sequences between UL9 and UvrB, another superfamily II member with
helicase-like activity, we were able to map the UL9
mutations on the structure of the UvrB protein and provide an
explanation for the observed phenotypes. Our results indicate that the
helicase function of UL9 is indispensable for viral replication,
supporting the hypothesis that UL9 is essential for unwinding the HSV-1
origin of replication in vivo. Furthermore, the data
presented provide insights into the mechanism of transdominance of the
UL9 helicase motif mutants.
*
This work was supported by United States Public Health
Service Grant AI21747.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Microbiology,
University of Connecticut Health Center, 263 Farmington Ave.,
Farmington, CT 06030. Tel.: 860-679-2310; Fax: 860-679-1239; E-mail:
Weller@NSO2.uchc.edu.
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