From the study of what dictates protein output from mRNAs, to blocking mRNA expression, McGill’s Jerry Pelletier has storied history of RNA research

Esteemed professor plays key role in founding of new McGill Centre for RNA Sciences

Jerry Pelletier, PhD, a Professor at McGill University’s Department of Biochemistry and Department of Oncology, and a member of the Rosalind and Morris Goodman Cancer Institute, is a distinguished RNA biology researcher who brings a unique and significant focus on the developing area of RNA research as a co-founder of the McGill Centre for RNA Sciences.

Professor Pelletier, co-author of 286 peer-reviewed publications and, recipient of the 2019 Robert Noble Award from the Canadian Cancer Society for outstanding achievements in basic biomedical cancer research, first developed an interest in RNA research in the final year of his undergraduate degree in Biochemistry at McGill. His initial interest was primarily due to developments in molecular biology tools that could provide insight into understanding and manipulating gene expression programs.

In 1988, Prof. Pelletier earned his PhD from McGill, having worked under the guidance of iconic Professor Nahum Sonenberg, PhD, who, had started his lab 10 years prior. Professor Pelletier would go on to complete his post-doctoral training at the Massachusetts Institute of Technology (MIT) Cancer Centre, in the lab of Professor David Housman, PhD, a prominent genetics researcher, conducting research on Wilms’ tumour, characterizing the WT1 tumour suppressor gene.

Early Research – Regulating protein outputs, IRESes, and synthetic mRNA molecules

Prof. Pelletier’s PhD thesis titled “Structure function relationships of mRNAs” focused on better understanding what features of an mRNA molecule dictate protein output.

“What we found at the time were a couple of things that are relevant to the interest of today's RNA therapeutics,” Prof. Pelletier explains. “We discovered that flanking the main region of an mRNA molecule, which makes the protein, are regulatory signals that controlled protein output. The results of this research were that we identified rules that dictate what the output from an mRNA would be.”

Fast forward to the current COVID-19 pandemic, and the translational aspect of Prof. Pelletier’s early research into these rules are now being used in vaccine development because developers want maximal protein output for each mRNA dose.

At the same time as the aforementioned early research in McGill laboratories, another discovery they made was a method for putting caps on mRNA molecules that were made in vitro, which was, as Prof. Pelletier recalls, “A major technological advancement at that time, because this is a special structural feature that needs to be put on an mRNA in order to get it to start making protein.”

Prof. Pelletier and his team were also studying how viruses, in particular polio, bypass regulatory signals that cellular mRNAs use, and, for the first time, they described the phenomenon of how poliovirus creates its own protein. Prof. Pelletier notes that, “What we had discovered was that the virus goes through a specialized mechanism: Instead of the protein synthesis machinery starting at the end of the RNA, the viral mRNA would internally recruit the protein synthesis machinery.”

This phenomenon was a major discovery in RNA research as the sequences that Prof. Pelletier and his team found made it possible to internally recruit the protein synthesis machinery at any spot that you desire to make synthetic mRNA molecules, which are used to make several proteins from a singular mRNA molecule, also known as internal ribosome entry sites (IRES).

Current research - Blocking expression of specific mRNA

Recently, Prof. Pelletier and his lab have been interested in blocking expression of specific mRNAs to inhibit the production of specific proteins at the level of the mRNA. They have identified natural products that do this in a very peculiar way - by acting as molecular glue or staples. The molecules interact with the RNA, but they also interact with an RNA binding protein that they lock onto the RNA and that acts as a roadblock to the protein synthesis apparatus.

“Creating these roadblocks, using this molecular glue, is an effective method for blocking the synthesis of proteins from an mRNA,” explains Prof. Pelletier. This phenomenon provides a new approach in the scientific domain and a new method for finding drugs that target RNA.”

With the launch of the McGill Centre for RNA Sciences, Prof. Pelletier hopes to continue his research in fundamental biology to potentially drug or target RNA in new ways, leading, directly or indirectly, to the development of RNA therapeutics as they apply to the development of novel anti-cancer drugs.


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