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Principal Investigator: Dmitri Ermolenko
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $594,440
Funding agency: National Institute of General Medical Sciences
The Central Dogma of molecular biology is that DNA is used to make mRNA, which in turn is used to make
proteins. Central to physiology of every live cell, translation of messenger RNA (mRNA) into protein is
catalyzed by the ribosome, structurally complex and dynamic macromolecular machine. Dysregulation of
translation plays an important role in a number of human diseases including cancer. While some fundamentals
of protein synthesis have been revealed, many molecular details of ribosomal translation remain unknown. For
example, it is unclear why some mRNAs are translated orders of magnitude more efficiently than the others,
and how mRNA structure regulates protein synthesis. My laboratory investigates molecular mechanisms of
translation by studying structural dynamics of the ribosome, and the role of mRNA secondary structure in
translation regulation. We use single-molecule microscopy and biochemical approaches to address the
following questions: (i) How does the small ribosomal subunit move along mRNA in search for the start site for
translation initiation in eukaryotes? (ii) How does the intrinsic compactness of mRNA and intramolecular
basepairing interactions formed by the 5' and 3' untranslated regions (UTRs) of mRNA regulate the efficiency
of protein synthesis in eukaryotes? (iii) How do mRNA stem-loop structures induce ribosome translation
pauses, which control expression of a number of proteins in bacteria, eukaryotes and eukaryotic viruses,
including Human Immunodeficiency Virus (HIV) and the cause of the COVID-19 pandemic, SARS-CoV-2? (iv)
How are structural dynamics of eukaryotic ribosome (in particular, rotational movements between the small
and the large ribosomal subunits) converted into the intricate process of protein synthesis? Our studies will
substantially contribute to establishing the molecular mechanisms of protein synthesis, and provide the basis
for the future development of antiviral and cancer therapies.
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