Jonathan Dinman

Virology (BSCI437).
Genetics I: Gene Expression (CBMG688F).
Graduate Virology (BSCI688).
Special Problems in Cell Biology and Molecular Genetics: Protein Translation (CBMG699Z).

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.

 2007

Jacobs, J.L., Belew, A.T., Rakauskaitė, R., and Dinman, J.D.* 2007. Identification of functional, endogenous programmed -1 ribosomal frameshift signals in the genome of Saccharomyces cerevisiae. Nucleic Acids Res. 35:165-74.
Baxter-Roshek, J.L., Petrov, A.N., and Dinman, J.D.* 2007. Optimization of ribosome structure and function by rRNA base modification. PLoS ONE. 2: e174.
Meskauskas, A., and Dinman, J.D.* 2007. Ribosomal protein L3: gatekeeper to the A-site. 2007. Molecular Cell 25: 877 - 888.
Plant, E.P., Nguyen, P., Russ, J.R., Pittman, Y.R., Nguyen, T., Quesinberry J.T., Kinzy, T.G., and Dinman, J.D.* 2007. Differentiating between near- and non-cognate codons in Saccharomyces cerevisiae. PLoS ONE 2: e517.
Swatkoski, S., Gutierrez, P., Ginter, J., Petrov, P., Dinman, J.D., and Fenselau, C. 2007. Integration of residue-specific acid cleavage into proteomic workflows. J. Proteome Res., 6: 4525-4527.
Chaudhuri, S., Vyas, K., Kapssi, P., Komar, A.A., Dinman, J.D., Barki, S., and Mazumder, B. 2007. Human ribosomal protein L13a is Dispensable for Canonical Ribosome Function but Indispensable for Efficient rRNA Methylation. RNA 13: 2224-2237. 

2008 

Swatkoski, S., Gutierrez, P., Ginter, J., Petrov, P., Dinman, J.D., and Fenselau, C. 2008. Evaluation of Microwave-Accelerated Residue-Specific Acid Cleavage for Proteomic Applications. J. Proteome Res. 7: 579-586.

Rakauskaitė, R. and Dinman, J.D. 2008. rRNA mutants in the yeast peptidyltransferase center reveal allosteric information networks and mechanisms of drug resistance. Nucleic Acids Res. 36: 1497 -1507.

Meskauskas, A., Russ, J.R., and Dinman, J.D. 2008. Structure/function analysis of yeast ribosomal protein L2. Nucleic Acids Res. 36: 1826-1835.

Liao, P.-Y., Gupta, P., Petrov, A.N., Dinman, J.D. and Lee, K.H. 2008. A new kinetic model reveals the synergistic effect of E-, P- and A-sites on +1 ribosomal frameshifting. Nucleic Acids Res 36: 2619-2629. PMID: 18344525

Belew, A.T., Hepler, N.L, Jacobs, J.L. and Dinman, J.D. 2008. PRFdb: A database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals. BMC Genomics 9: 339.

Stupina, V., Meskauskas, A., McCormack, J.C., Yingling, Y.G., Shapiro, B.A., Dinman, J.D., and Simon, A.E. 2008. The 3' proximal translational enhancer of turnip crinkle virus binds to 60S ribosomal subunits. RNA 14: 2394-2406

Meskauskas, A. and Dinman, J.D. 2008. The N-terminal extension of ribosomal protein L3 helps coordinate large subunit-associated functions in eukaryotes and Archaea. Nucleic Acids Research 36: 6187-6198.

Petrov, A.N., Meskauskas, A., Roshwalb, S.C., and Dinman, J.D.  2008. Yeast ribosomal protein L10 helps coordinate tRNA movement through the large subunit. Nucleic Acids Research 36: 6187-6198.6.

Plant, E.P. and Dinman, J.D.  2008. The role of programmed -1 ribosomal frameshifting in coronavirus propagation. Frontiers in Bioscience: a Journal and Virtual Library. 13: 4873-81.

A.B. Philosophy, Oberlin College, 1980

Ph.D. Johns Hopkins University, 1988