image: Allan Jacobson, recipient of the 2023 Gruber Prize for Genetics view more
Credit: Gruber Foundation
Every plant, every animal, every human depends on mRNA to accurately translate the DNA of their genetic code into proteins, the building blocks of life.
Right now, millions of mRNA molecules are at work in our bodies, in a complex series of molecular dances. Mistakes are made, leading to potentially toxic proteins which can inhibit the normal functioning of cells and normal human development.
The body’s quality control of this process was identified and described by Lynne Maquat and Allan Jacobson in the 1980s and 90s. They showed how our cells destroy faulty mRNA molecules. They demonstrated that messenger RNA is much more than a passive carrier of genetic code. It plays a central role in gene regulation.
They named this quality control process nonsense-mediated mRNA decay (NMD).
Their work informed our understanding of fundamental life processes, and enables the use of mRNA as a tool today in vaccines and medicines. They have each gone on to use it as a target for therapeutics.
Maquat’s lab is investigating the role of NMD in, and treatments for, Fragile X syndrome, the commonest single gene cause of intellectual disability and autism.
Jacobson founded a company that is now trialling treatments for Duchenne muscular dystrophy (DMD).
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Working with yeast, Allan Jacobson, PhD, of the University of Massachusetts Chan Medical School, identified the core components of the nonsense mediated mRNA decay pathway. He was also able to demonstrate the role this pathway plays as a quality control checkpoint for mRNAs with a premature stop codon, whether due to a mutation or gene expression errors.
Lynne Maquat, PhD, of the University of Rochester School of Medicine and Dentistry, studied patients with haemolytic diseases. She demonstrated the importance of nonsense-mediated mRNA decay in humans by showing that mRNAs with a premature stop codon were more unstable.
She went on to show that NMD acts to eliminate faulty transcripts that are the byproduct of routine errors in human gene expression.
She also found that cells use NMD to adapt to stresses in the cell such as differentiations, DNA damage including the impact of chemotherapy, and nutrient deprivation through the fine-tuning of approximately five to ten per cent of mRNAs.
The two researchers will share the US$500,000 Gruber Prize for Genetics which has been awarded every year since 2001. Australian-born Nobel Laureate Elizabeth Blackburn received the Prize in 2006.
Read the Gruber Foundation media release at https://gruber.yale.edu/2023-gruber-genetics-prize
Read about the Foundation at https://gruber.yale.edu/foundation
Congress media releases at https://www.scienceinpublic.com.au/genetics