Rate At Which Genetic Code Read May Offer New Drug Targets

Jeff Coller, PhD  Associate professor Division of General Medical Science Associate director, The Center for RNA Molecular Biology, Case Western Reserve University School of MedicineMedicalResearch.com Interview with:
Jeff Coller, PhD
  Associate professor
Division of General Medical Science
Associate director, The Center for RNA Molecular Biology,
Case Western Reserve University School of Medicine

MedicalResearch: What is the background of this study?

Dr. Coller: There are a diverse number of half-lives for any individual messenger RNA (mRNA). The range of those half-lives is from seconds to hours. What the field has wanted to know for 30 years is how those rates are regulated, and there has been considerable anecdotal and real evidence that sequences in untranslated regions (UTRs) could regulate decay, but it doesn’t explain all of the half-lives that are observed for all messages. In addition, we have known mRNAs that are translated better are more stable than mRNAs that are translated poorly, so those pieces together led to the discovery.


MedicalResearch: What are the main findings of the study?

Dr. Coller: We can explain a large number of mRNA half-lives based on codon usage. We found that every codon within the genetic code is not created equal. The degeneracy in the genetic code is not only there because of the mathematics, but it is also there because it sets speed limits for the ribosome. So some codons are read faster than others. The rate at which those codons are read is cumulative across the entire span of the message and ultimately affects the overall level of protein and feeds back into mRNA decay. Codon composition sets a speed limit for translation rate, and that affects protein expression and mRNA decay rate. Those are the fundamental findings.

MedicalResearch: What can clinicians take away from this report?

Dr. Coller: Now that we recognize that protein synthesis rate is determined by codon composition, which is a novel finding, there may be disease states that activate at that level. For example, it would be possible to have a disease state where the rate of protein synthesis was changed, but wouldn’t be observed as a mutation within that particular gene. The machinery that sets that rate of translation could be altered, and that may have profound implications to medicine. This opens a whole new category of potential targets for drugs, as well as where disease states will arise.

MedicalResearch: What are the recommendations for future research?

Dr. Coller: What will have to be determined will be whether the rates of protein synthesis change in disease states. Our study shows that the rate of protein synthesis is determined by the levels of transfer RNAs (tRNA). What we will have to determine is whether there are disease states where tRNA concentrations have changed within the cell. In addition, can we target the machinery that sets the rate of translation in order to alleviate a disease state? That will be the future research — how codon optimality relates to human health. My lab will investigate extensively how speed limits are controlled in human cells and different cell types and in different disease states. In the scientific community in general, lots of researchers will conduct their own investigations into the rate of at which codons are read.

Citation:

Codon optimality is a major determinant of mRNA stability
Presnyak, Vladimir et al.

Cell , Volume 160 , Issue 6 , 1111 – 1124

 

MedicalResearch.com Interview with: Jeff Coller, PhD Associate professor (2015). Rate At Which Genetic Code Read May Offer New Drug Targets 

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