Ribosomal Translocation as a Regulatory Point in Translational Control

Jason Feinberg

Appointment Period: 2003-2004, Grant Year: [19]

It has been shown that modification levels of transfer ribonucleic acids (tRNAs) in malignant tumors varies substantially to that of normally growing cells. Inhibition of translocation elicits slow growth and lethal phenotypes while an acceleration of this process could cause miscoding. A hallmark of cancer is unregulated cell proliferation, which requires an overall increase in the translational machinery responsible for protein biosynthesis. The ability to synthesize proteins in a rapid and highly accurate fashion is critical to cell growth. In eukaryotes it has been demonstrated that enzymes known to modify tRNAs have been found at elevated levels in several types of cancer cells, i.e. colon cancer cells, leukemic cells and pancreatic cancer cells.

Our research focuses on understanding the molecular mechanism of this process. Modified tRNAs are found in several types of cancer cells yet their role in the translation apparatus is not fully understood. My studies have shown that modifications to the tRNA can have a severe effect on translocation. Additionally, in prokaryotes several antibiotics interact with the bacterial ribosome to arrest protein synthesis. Cancer patients, during treatment are severely immunocompromised and are more susceptible to infections; bacterial and parasitic, characterization of the molecular mechanism of translation will help guide rational design of more effective therapeutic agents.

Feinberg JS, Joseph S. Identification of molecular interactions between P-site tRNA and the ribosome essential for translocation. Proc Natl Acad Sci USA. (2001) 98:11120-5. PMID: 11562497; PMCID: PMC58693.

Studer SM, Feinberg JS, Joseph S. Rapid kinetic analysis of EF-G-dependent mRNA translocation in the ribosome. J Mol Biol. (2003) 327:369-81. PMID: 12628244.

Feinberg JS, Joseph S. A conserved base-pair between tRNA and 23 S rRNA in the peptidyl transferase center is important for peptide release. J Mol Biol. (2006) 364:1010-20. PMID: 17045291.

Ali IK, Lancaster L, Feinberg J, Joseph S, Noller HF. Deletion of a conserved, central ribosomal intersubunit RNA bridge. Mol Cell. (2006) 23:865-74. PMID: 16973438.

Feinberg JS, Joseph S. Ribose 2'-hydroxyl groups in the 5' strand of the acceptor arm of P-site tRNA are not essential for EF-G catalyzed translocation. RNA. (2006) 12:580-8. PMID: 16489185; PMCID: PMC1421097.