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Faculty
 Sandra
K. Weller
Professor and Chair, Molecular, Microbial & Structural Biology
UCHC Board of Trustees Distinguished Professor, 2007
weller@nso2.uchc.edu
Areas of Interest:
HSV-1 and -2 are large DNA virus which are responsible for oral and
genital infections, sight-threatening ocular infections and brain
infections which can be life threatening. Our laboratory uses genetic,
biochemical, biophysical, structural and molecular approaches to
elucidate mechanisms of synthesis, maturation and cleavage and packaging
of viral genomes. One of our goals is to identify antiviral targets
which can be exploited to develop strategies for controlling viral
infections. Projects in the lab are diverse and include virus-host
interactions important for the formation of replication compartments
within the nucleus of infected cells; structure function analysis of two
viral helicases; structure-function analysis of the zinc binding domain
of the HSV-1 primase; analysis of the role of recombination in viral DNA
replication and genome maturation and the analysis of the machinery
involved in cleavage and packaging of viral genomes into preformed
procapsids. Important recent discoveries include :
- The identification and characterization of a novel viral
recombinase.
- The realization that host cell recombination and repair proteins
are involved in HSV DNA synthesis.
- The discovery that host chaperones are rearranged in infected
cells into foci which act as quality control mechanisms for the
production of properly folded proteins.
- The finding that the initiation helicase-origin binding protein
UL9 is degraded during infection in a ubiquitin mediated pathway.
- The further characterization of the interdependence of the
helicase and primase subunits with each other.
Lab Rotation Projects:
The role of the cellular DNA damage response in the Herpes Simplex
Virus Life Cycle.
It is becoming clear that viruses have evolved elaborate interactions
with the cellular repair, recombination and checkpoint machinery in
order to create an environment conducive to their own replication. The
host cell’s DNA damage machinery is alert for perturbations in DNA which
could lead to genetic instability. After infection, some of this
machinery is inactivated by the virus in attempt to remove obstacles to
productive infection; however, other components are utilized by the
virus to promote viral DNA replication. In this project, aspects of this
fascinating cat and mouse game will be examined.
Cleavage and Packaging of Herpes Simplex Virus genomes.
Capsid assembly and genome encapsidation are critical aspects in the
life cycle of any virus. Our goal is to gain a better understanding of
the processes by which head to tail concatemeric DNA molecules are taken
up into preassembled capsids. We have recently provided the first
evidence that HSV capsids contain disulfide bonds which may be important
for viral assembly and encapsidation. This rotation project will involve
the introduction of mutations into the conserved cysteine residues of
capsid proteins to determine whether proper disulfide bond formation is
important for during infection.
Selected Publications:
Livingston, C. M., D. E. Wilkinson, and S. K. Weller. 2007.
Preprelicative sites of Herpes Simplex Virus Type 1. J. of Virol.
Manuscript in preparation.
Chattopadhyay, S., and S. K. Weller. 2007. Protein-protein interactions
between the N- and C terminal fragments of UL9. J. of Virol. Manuscript
in preparation.
Chen, Y., P. Bai, and S. K. Weller. 2007. The HSV-1 helicase-primase
require ssDNA to load and unwind. J. Biol. Chem. Manuscript in
preparation.
Chen, Y., C. M. Livingson, S. D. Carrington-Lawrence, P. Bai, and S. K.
Weller. 2007. A Mutation in the Human Herpes Simplex Virus Type I UL52
Zinc Finger Motif Results in Defective Primase Activity but Can Recruit
Viral Polymerase and Support Viral Replication Efficiently. J. of Virol.
Manuscript submitted.
Saffran, H.A., Pare, J.M. Corcoran, J.A., Weller, S.K. and J.R. Smiley.
2007. Herpes simplex virus eliminates host mitochondrial DNA. Embo J.
8:188-93.
Wilkinson, D. E., and S. K. Weller. 2006. Herpes Simplex Virus Type I
Disrupts the ATR-Dependent DNA Damage Response During Lytic Infection.
Journal of Cell Science J Cell Sci. 119:2695-703.
Chattopadhay, S., and Chen, Y., SK Weller. 2006. The two helicases of
herpes simplex virus type 1 (HSV-1). Front Biosci. 2006;11:2213-23.
Chattopadhay, S., and SK Weller. 2006. The DNA binding activity of the
HSV-1 origin binding protein, UL9, can be modulated by sequences in the
N-terminus: Correlation between transdominance and DNA binding. J. Virol.
80:4491-500.
Burch A.D. and S.K. Weller. 2005 The HSV-1 DNA polymerase requires the
mammalian chaperone HSP90 for proper localization to the nucleus. J. of
Virol. 79:10740-9.
Pierce, AT, J. DeSalvo, TP Foster, A. Kosinski A, SK WelIer, and WP
Halford. 2005. nterferon-b and interferon-g synergize to repress herpes
simplex virus type 1 DNA synthesis and nucleocapsid assembly. J. of
Virol., 2005. J Gen Virol ; 86: 2421-2432.
Chen, Y. S.D. Carrington-Lawrence, P. Bai and S.K. Weller. 2005.
Mutations in the Putative Zinc-Binding Motif of UL52 Demonstrate a
Complex Interdependence between the UL5 and UL52 Subunits of the Human
Herpes Simplex Virus Type 1 Helicase/Primase Complex. J. Virol.
29:9088-9096.
Reuven, N.B. and S.K. Weller 2005 The Herpes simplex virus type 1 single
strand DNA binding protein ICP8 enhances the nuclease activity of the
UL12 alkaline nuclease by increasing its processivity. J. Virol. 79:
9356-9358.
Wilkinson, D. E., and S. K. Weller. 2005. Inhibition of the HSV-1 DNA
Polymerase Induces the Hyperphosphorylation of Replication Protein A and
Its Accumulation at S Phase-specific Sites of DNA Damage During
Infection. J. Virol. 79: 7162-71.
Reuven, N.B., S. Willcox, J.D. Griffith, and S.K. Weller, 2004 Catalysis
of strand exchange by the HSV-1 UL12 and ICP8 proteins: potent ICP8
recombinase activity is revealed upon resection of dsDNA substrate by
nuclease. Journal of Molecular Biology, 342:57-71.
Burch A. and Weller SK. 2004. Nuclear sequestration of cellular
chaperone and proteasomal machinery during HSV-1 infection. J Virol,.
78(13): p. 7175-85.
Reuven, NB, Antoku, S, and Weller SK. 2004. UL12.5 retains all known
enzymatic functions of UL12 including strand exchange but is unable to
substitute for the lack of UL12 because it lacks a nuclear localization
signal. J Virol, 2004. 78(9): p. 4599-608.
Wilkinson, D. E., and S. K. Weller. 2004. Recruitment of Cellular
Recombination and Repair Proteins to Sites of HSV-1 DNA Replication is
Dependent upon the Composition of Viral Proteins within Prereplicative
Sites and Correlates with the Induction of the DNA Damage Response. J.
of Virol. 78:4783-96.
Wilkinson, D. E., and S. K. Weller. 2003. The Role of DNA Recombination
in Herpes Simplex Virus DNA Replication. IUBMB Life 2003 55: 451-458.
Marintcheva, B. and S. K. Weller, 2003. Transdominant and Potentiating
Mutants of UL9, the HSV-1 origin binding protein, suggest that levels of
UL9 protein may be regulated during infection. J. Virol. 77: 9630-51.
Prezch, A.J., D. Yu and Weller, S.K. 2003. Point mutations in exon I of
the Herpes Simplex Virus putative terminase subunit, UL15, indicate that
the most conserved residues are essential for cleavage and packaging. J.
of Virol. 77: 9613-21.
Reuven, N.B., Staire, A.E., Myers, R.S., and Weller, S.K. 2003. The
Herpes Simplex Virus-1 Alkaline Nuclease and Single-strand DNA Binding
Protein Mediate Strand Exchange in vitro. J Virol 77: 7425-33.
Carrington-Lawrence, S. D., and Weller, S. K. 2003. Recruitment of
Polymerase to Herpes Simplex Virus Type 1 Replication Foci in Cells
Expressing Mutant Primase (UL52) Proteins. J Virol 77: 4237-4247.
Marintcheva, B. and S. K. Weller. 2003. Helicase motif Ia is involved in
single-strand DNA-binding and helicase activities of the herpes simplex
virus type 1 origin-binding protein, UL9. J Virol 77: 2477-88
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