Professor [and Affiliate of Chemistry & Biochemistry]
Office Phone: (301) 405-0918
Fax: (301) 314-9489
Office Address: 2135 Microbiology Building
Graduate Virology (BSCI688).
Special Problems in Cell Biology and Molecular Genetics: Protein Translation (CBMG699Z).
Graduate Program Affiliations
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.
2016 University of Maryland Integrated Life Sciences program Mentor of the Year Award.
2015 Committee on Institutional Cooperation Department Executive Officers Fellowship.
2014 - 2015 Committee on Institutional Cooperation Academic Leadership Program Fellowship.
2014 Summer Research and Scholarship Award, UMD Graduate School. 2014.
2014. Summer Research and Scholarship Award, UMD Graduate School
2012 - 2013. UMD ADVANCE Leadership Fellow.
2011. UMIACS New Research Frontiers Award.
2007. Finalist, Life Sciences Invention of the Year , University of Maryland.
2005. Thomas Alva Edison Patent Award.
2004. University of Maryland College of Life Sciences Faculty Excellence Award for Research.
2004. Outstanding Invention of 2003, Life Sciences. University of Maryland Office of Technology Commercialization, Research and Graduate Studies.
2003. Merck-Frosst Lecture, University of Montreal.
2002. University of Maryland, College of Life Sciences Workstation Deployment Program Faculty Technology Matching Funds Award.
1995-96. American Cancer Society Junior Faculty Research Award
1992-95. National Institutes of Health Staff Fellowship
1989-92. Intramural Research Training Award Fellow, NIH
1989. Fredrick B. Bang Award, Department of Immunology and Infectious Diseases, JHU.
1987-89. Post Certified Scholarship Award, Johns Hopkins University.
1986. Tuition Scholarship Award, Johns Hopkins University.
1984. Sigma Xi Award, Johns Hopkins School of Hygiene and Public Health.
Faculty of 1000 (2019 – Present).
Journal of Biological Chemistry (2015 – Present).
Nucleic Acids Research (2007 – Present).
Infection and Drug Resistance (2018 – Present).
A.B. Philosophy, Oberlin College, 1980
Ph.D. Johns Hopkins University, 1988