2012 Rosenstiel Award Lecture
Thursday, March 29, 2012, 4:00 PM
The 2012 Rosenstiel award winner, Dr. Nahum Sonenberg of McGill University, is a well-deserving recipient of this honor. Dr. Sonenberg received his Ph.D. in 1976 at the Weizman Institute of Science. He then worked with Aaron Shatkin, where he discovered the translation initiation factor responsible for binding the 5’ cap of mRNA, eukaryotic Initiation Factor 4E (eIF4E); He has studied translation ever since. Although his lab focuses on understanding how the cell achieves precise control of translation initiation, this line of investigation has led to discoveries affecting a wide variety of systems. His lab has made key discoveries in cancer, obesity, virology, memory consolidation and how translation control plays a role in regulating these disparate processes.
In 1988, the Sonenberg lab made the groundbreaking discovery (Nature 1988, http://www.ncbi.nlm.nih.gov/pubmed/2839775) that the uncapped viral mRNA from poliovirus recruits the ribosome to internal regions of the 5’ untranslated region (UTR). These sites have since been renamed internal ribosomal entry sites (IRESs). This finding was exciting since eukaryotic translation initiation typically requires the 5’ cap on an mRNA for eIF4E binding which subsequently recruits translation initiation machinery. Until this time, the only mechanism of translation initiation was through the binding of eIF4E to the 5’ cap of mRNAs. Sonenberg’s discovery that some mRNA has a mechanism to bypass the need for eIF4E binding and thereby avoiding translation control mechanisms started a new line of investigation in the translation field. Along with discovering IRESs, this paper established an in vitro and an in vivo assay to study cap-independent translation initiation. These assays are still used widely to test for IRES activity of mRNA UTRs.
Since that initial discovery, it has been found that many viruses contain IRES sequences in the UTR of mRNA that direct translation of viral proteins. Some viruses, including poliovirus, are able to hijack eukaryotic translation machinery by cleaving factors necessary for canonical cap-dependent translation initiation, but dispensable for IRES translation. In this way, viral mRNAs are able to outcompete eukaryotic mRNAs for ribosome binding and in many cases become the most abundant transcript being translated.
Since the discovery of viral IRESs, many labs, including the Sonenberg lab, have discovered that some cellular genes also use IRESs to bypass the typical translation initiation control mechanisms. These genes are capable of translating even when the cell is actively shutting down translation. One such cellular IRES-containing mRNA is the insulin receptor message, the IRES I study in the Marr lab. Using assays similar to those first used in the 1988 paper published by the Sonenberg lab, I am exploring the necessity for the various initiation factors and IRES sequences required for efficient translation of insulin receptor in Drosophila melanogaster and mammalian cells.
The discovery that Dr. Sonenberg made in 1988 is only one example of the elegant research his lab has produced and continues to pursue.