Dorothea L. Sawicki, Ph.D.
Professor Vice Provost, Health Science Affairs & University Accreditation
Mechanisms used by alphaviruses and RNA viruses to control the synthesis of viral RNA
E-mail Address: email@example.com
Dr. Sawicki studies the mechanisms used by alphaviruses and a related group of animal
and plant RNA viruses to control the synthesis of viral RNA. These viruses are members
of the Sindbis superfamily and share extensive homology in the sequences of their
polymerase proteins with the animal alphaviruses, Sindbis virus and Semliki Forest
virus. Alphaviruses are of general interest because they produce disease in a variety
of animals, including humans, and because they replicate in invertebrates as well
as vertebrates. Her studies focus on the synthesis of the viral template or minus-strand
RNA that is needed to amplify the viral information, to form progeny genomes, and
to allow the virus to take over the synthetic machinery of the cell. In nature, a
balance exists between alphaviruses and their invertebrate hosts such that there is
limited replication of the virus with survival of the host. This phenomenon of viral
persistence has been studied using a collection of temperature sensitive mutants that
fail to cause the synthesis of viral RNA at nonpermissive temperature, in particular
mutants that are defective specifically in minus-strand RNA synthesis. The mechanisms
responsible for regulating the synthesis of minus-strand RNA and for determining the
maximal rate of viral RNA synthesis are being studied. Mutations responsible for defects
in viral RNA synthesis are being mapped to particular viral proteins by constructing
recombinant mutant genomes in infectious cDNA clones of Sindbis virus and by sequencing
those regions expressing functional defects. Other studies use in vitro RNA synthesizing
systems to elucidate the nature of the viral replication complexes and the mechanism
of alphavirus RNA synthesis. The essential role of polyprotein forms of the viral
polymerase proteins in minus strand synthesis but not in genome or mRNA synthesis,
proposed by this lab, is being pursued using an in vitro reconstitution system to
probe functions necessary for promoter recognition, elongation, temporal regulation
of minus strand synthesis and internal initiation by the viral transcriptase to form
a subgenomic mRNA.
Prior grant funding:
NIH - Alphavirus minus strand RNA synthesis and Rnase L
Dé, I., Fata, C.L., Sawicki, S.G., and Sawicki, D.L. (2003) Functional analysis of nsP3 phosphoprotein mutants. J. Virol. 77(24):13106-16.
Sawicki, D.L., Silverman, R.H., Williams, B.R., and Sawicki, S.G. (2003) Alphavirus minus-strand synthesis and persistence in mouse embryo fibroblasts derived from mice lacking RNase L and protein kinase R. J. Virol. 77: 1801-1811.
Fata, C.L., Sawicki, S.G., and Sawicki, D.L. (2002) Modification of Asn374 of nsP1 suppresses a Sindbis virus nsP4 minus-strand polymerase mutant. J. Virol. 76: 8641-8649.
Fata, C.L., Sawicki, S.G., and Sawicki, D.L. (2002) Alphavirus minus-strand RNA synthesis: identification of a role for Arg183 of the nsP4 polymerase. J. Virol. 76: 8632-8640.
Sawicki, D., Wang, T., and Sawicki S. (2001) The RNA structures engaged in replication and transcription of the A59 strain of mouse hepatitis virus. J. Gen. Virol. 82: 385-396.
Sawicki, S.G. and Sawicki, D.L. (1998) A New Model for Coronavirus Transcription. Advances in Experimental Medicine, 440: 215-220.
Sawicki, D.L and Sawicki, S.G. (1998) Role of the nonstructural polyproteins in alphavirus RNA synthesis. Advances in Experimental Medicine, 440: 187-198.