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Nicholas R. Guydosh, Ph.D., Stadtman Tenure-Track Investigator

Photo of Nicholas Guydosh.
Scientific Focus Areas: Biomedical Engineering and Biophysics, Computational Biology, Genetics and Genomics, Molecular Biology and Biochemistry, RNA Biology

Professional Experience

  • Postdoctoral Fellow, Johns Hopkins University School of Medicine, 2009-2016
  • Ph.D., Stanford University, 2009
  • M.Phil, University of Cambridge, 2003
  • A.B., Harvard University, 2001

Research Goal

We seek to discover how cells control the expression of genes during translation by the ribosome. We’re interested in both the mechanisms that underlie the basic steps of translation—particularly termination and recycling—and how these processes are regulated to carry out cellular functions.

Current Research

The translation of the genetic code is a highly regulated process that is fundamental to life. All cells have evolved elaborate mechanisms for determining which RNA messages get translated, how frequently and where they are translated, and whether errors occur. We employ multi-disciplinary approaches such as ribosome profiling, biochemical techniques, and computational tools to investigate how translation is regulated to control the expression of genes in yeast and mammalian cultured cells. We’re also developing single-molecule fluorescence methods to address mechanistic questions about ribosome function.

We recently discovered that failure to properly remove (recycle) ribosomes from mRNAs at stop codons leads to reinitiation of translation in 3’UTRs and the production of short peptides. We’re now investigating the mechanism of this non-canonical process and potential functions for the peptide products in helping cells respond to stress, such as nutrient starvation and viral infection. We’re also interested in the “rescue” process that takes place when ribosomes arrest after translation of particular sequences, such as the poly(A) tail of prematurely polyadenylated mRNAs.

We’re also pursuing general questions of how translation is coupled to mRNA decay and protein localization.

Applying our Research

The ribosome is central to gene expression so our basic work on ribosome function is critical for developing models of disease. In particular, we are examining how changes in the translational machinery during viral infection lead to the production of non-canonical peptides that can be used during the innate immune response. We are also looking at how environmental stress and changes in nutrient levels alter the translational program of a cell. Outcomes of this research will help guide the development of new therapies in the areas of infectious disease, aging, and cancer.

Select Publications

40S ribosome profiling reveals distinct roles for Tma20/Tma22 (MCT-1/DENR) and Tma64 (eIF2D) in 40S subunit recycling.
Young DJ, Meydan S, Guydosh NR.
Nat Commun (2021 May 20) 12:2976. Abstract/Full Text
Activation of the antiviral factor RNase L triggers translation of non-coding mRNA sequences.
Karasik A, Jones GD, DePass AV, Guydosh NR.
Nucleic Acids Res (2021 Jun 21) 49:6007-6026. Abstract/Full Text
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Research in Plain Language

Proteins are made in the cell by a large molecular complex called the ribosome. Our research is aimed at understanding how the ribosome works, particularly the cases where it makes proteins that are not normally produced in cells. A better understanding of these processes is important for understanding how cells resist infection and avoid becoming cancerous.