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Lee
Gehrke,
Ph.D.
Massachusetts Institute of Technology
Exploiting an Evolutionary Omission in Pathogenic RNA Viruses: Understanding the Advantages of BeingNon-polyadenylated.
The identification of features that are pathogen-specific and sensitive to therapeutic
agents is fundamental to treating infectious human diseases. This proposal focuses
on a feature common to a wide range of pathogenic RNA viruses: the absence of
poly(A) tails on the viral messenger RNAs. Viruses included in this group include
dengue hemorrhagic fever, West Nile, Japanese and St. Louis encephalitis, and
rotaviruses. We propose to define the molecular mechanisms enabling the viral
mRNAs to circumvent the functional requirement for poly(A) tails that is shared
among cellular mRNAs. The ultimate goal is to develop a unified approach for
drug therapy.
Brief Description of Proposed Research: With exceedingly few exceptions,
cellular messenger RNAs (mRNAs) terminate in poly(A) tails, which are now
known to regulate the efficiency of cellular mRNA translation. RNA-protein and
protein-protein interactions between the 5’ cap structure and the 3’ poly(A)
facilitate ribosome binding during the initiation stage of protein biosynthesis. In
contrast, the mRNAs of a number of pathogenic RNA viruses share a common
feature that distinguishes them from cellular mRNAs: they lack 3’ poly(A) tails, yet
are in fact stable and fully capable of supporting protein synthesis. Our goal is to
define the common mechanism(s) that allow these viral mRNAs to circumvent the
poly(A) requirement during mRNA translation. Our approach is two-fold. First,
we propose to identify nucleotide sequences or structures in the 5' and/or 3'
untranslated regions of the viral RNAs that both distinguish them from cellular
mRNAs and release them from dependence on the poly(A) tail. Second, we
propose to define RNA binding proteins that interact with these untranslated
regions, thereby allowing them to translate efficiently without the poly(A) tail. This
experimental strategy will provide important new insights into mechanisms of viral
gene statement and will identify new targets for therapeutics to treat viruses that
cause significant morbidity and mortality worldwide.
This proposal has three Specific Aims. The experiments will focus on the 5’ and 3’
untranslated regions of the viral mRNAs, which very likely contribute to the
translation-level regulation. The first Specific Aim will be to use bioinformatics
approaches to compare the 5’ and 3’ untranslated regions of the viral RNAs in an
effort to identify nucleotide sequences or structures that may be related among this
diverse group of viruses. The second Specific Aim will use genetic approaches to
identify nucleotides that are required for efficient viral mRNA translation. The third
Specific Aim will be to apply biochemical methods toward the identification of
host factors and/or viral proteins that bind to the viral RNAs and influence
translation.
Contact
Dr. Gehrke.
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