Research Interests: Post-transcriptional control of gene expression.
Dinman Lab Homepage
Virology - The maintenance of correct translational reading frame is
fundamental to the integrity of the protein synthetic process, and ultimately
to cell growth and viability. Despite this, it has been demonstrated that certain
viruses utilize specific signals on their mRNAs that induce elongating ribosomes
to shift reading frame. The highly controlled efficiencies of PRF events ensure
that the proper stoichiometric ratio of viral structural to enzymatic proteins
are available for viral particle assembly. Changing frameshifting efficiencies
alters this ratio, preventing proper viral particle assembly and interfering
with virus propagation. Thus, programmed ribosomal frameshifting presents a
promising new target for anti-viral pharmacological intervention. We are characterizing
a series of yeast mutants and drugs in order to identify new targets for antiviral
therapies. We are also working to create a reverse genetic system for a dsRNA
virus of yeast.
Ribosome Structure & Function - One important function of the ribosome
is to faithfully maintain translational reading frame. Viral mRNA signals that
abrogate this function by programming ribosomes to shift frame have proved to
be of tremendous utility in elucidating the molecular mechanisms underlying
this essential task. The newly available atomic resolution structures of ribosomes
mark a critical milestone in the quest to link ribosome structure with function,
and our studies on PRF have begun to link ribosome structure with translational
frame maintenance. We have shown that both the biophysical interactions between
ribosomal proteins rRNAs and tRNAs, and the biochemical properties of ribosome-associated
enzymatic activities are both important for proper reading frame maintenance.
On a broader scale, our work also is consistent with the hypothesis that communication
between the different functional centers of the ribosome is critical for coordinating
ribosome structure with its various functions. Of particular interest, recent
structural analyses of mutants that we had previously identified as affecting
frameshifting reveals that they correspond to critical points of contact between
specific ribosomal components. This positions us for to conduct reverse genetic
studies linking ribosome structure with function.
Regulation of Gene Expression - Since "biological systems tend to
use whatever works", there is no reason to believe that programmed ribosomal
frameshifting is exclusively utilized by viruses. Based on this philosophy,
we are pursuing a bioinformatic program designed to identify functional programmed
-1 ribosomal frameshift signals in the genomic databases. This effort employs
a combination of computational, DNA microarray, and traditional "wet lab"
approaches. We have found that programmed ribosomal frameshift signals can act
as mRNA suicide elements, suggesting that PRF is used to post-transcriptionally
regulate the abundance of specific mRNAs and their encoded protein products.
The reverse side of this coin is the question of how viruses have evolved to
circumvent this regulatory mechanism, allowing them to utilize programmed ribosomal
frameshifting without having their mRNAs degraded.
Recent Publications
Meskauskas,A., Baxter,J.L., Carr,E.A., Yasenchak,J., Gallagher,J.E., Baserga,S.J.,
and Dinman,J.D. (2003). Delayed rRNA processing results in significant ribosome
biogenesis and functional defects. Mol. Cell Biol. 23, 1602-1613.
Plant, E.P., Muldoon Jacobs, K.L., Harger, J.W., Meskauskas, A., Jacobs, J.L.,
Baxter, J.L., Petrov, A.N., Dinman, J.D. The 9-Å solution: How mRNA pseudoknots
promote efficient programmed -1 ribosomal frameshifting. RNA (9), 168-174 (2003).
Harger,J., Meskauskas,A. & Dinman,J. An 'integrated model' of programmed
ribosomal frameshifting. Trends Biochem. Sci. 27, 448 (2002). [ COVER ]
Goss,K.T. et al. New targets for antivirals: the ribosomal a-site and the factors
that interact with it. Virology 300, 60 (2002).
Dinman,J.D. et al. The frameshift signal of HIV-1 involves a potential intramolecular
triplex RNA structure. Proc. Natl. Acad. Sci. U. S. A 99, 5331-5336 (2002).
Smith,M.W., Meskauskas,A., Wang,P., Sergiev,P.V. & Dinman,J.D. Saturation
mutagenesis of 5S rRNA in Saccharomyces cerevisiae. Mol. Cell Biol. 21, 8264-8275
(2001).
Meskauskas,A. & Dinman,J.D. Ribosomal protein L5 helps anchor peptidyl-tRNA
to the P-site in Saccharomyces cerevisiae. RNA. 7, 1084-1096 (2001).
Harger,J.W., Meskauskas,A., Nielsen,J., Justice,M.C. & Dinman,J.D. Ty1 retrotransposition
and programmed +1 ribosomal frameshifting require the integrity of the protein
synthetic translocation step. Virology 286, 216-224 (2001).
Hudak,K.A., Hammell,A.B., Yasenchak,J., Tumer,N.E. & Dinman,J.D. A C-terminal
deletion mutant of pokeweed antiviral protein inhibits programmed +1 ribosomal
frameshifting and Ty1 retrotransposition without depurinating the sarcin/ricin
loop of rRNA. Virology 279, 292-301 (2001).
Dinman,J., Ruiz-Echevarria,M., Wang,W. & Peltz,S. The case for the involvement
of the Upf3p in programmed -1 ribosomal frameshifting. RNA. 6, 1685-1686 (2000).