Lynne E. Maquat, Ph.D., the founding director of the Center for RNA Biology at the University of Rochester, was honored with the 2021 Wolf Prize in Medicine. The acclaimed international award is given to outstanding scientists from around the world for achievements that benefit mankind.
Maquat was selected for “fundamental discoveries in RNA biology that have the potential to better human lives.” She has spent her career deciphering the many roles that RNA plays in sickness and in health, and is well known for her discovery of nonsense-mediated mRNA decay or NMD. One of the major surveillance systems in the body, NMD protects against mistakes in gene expression that lead to disease. Maquat’s lab also revealed that NMD helps our cells adjust to changes in development and in their environment, and more rapidly respond to certain stimuli.
Maquat shares the award with Joan Steitz, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry at Yale School of Medicine and Adrian Krainer, Ph.D., St. Giles Foundation Professor and Cancer Center Deputy Director of Research at Cold Spring Harbor Laboratory. Steitz and Krainer were also honored for discoveries in RNA biology.
The Wolf Foundation, which celebrates exceptional achievements in the sciences and the arts, is based in Israel, where Maquat’s quest to unravel the intricacies of NMD began. In 1980 she traveled to Jerusalem to retrieve bone marrow samples from four children suffering from thalassemia major, the most severe form of the inherited blood disorder thalassemia. Maquat wanted to learn why the children’s marrow contained no beta-globin protein, which is necessary for the oxygen-carrying function of red blood cells. Her 1981 breakthrough manuscript, “Unstable beta-globin mRNA in mRNA-deficient beta0 thalassemia,” published in Cell, was the first to reveal the role of NMD in human cells and how it can lead to disease.
“Lynne’s work on nonsense-mediated mRNA decay is the bedrock of an ever-growing body of research on how mRNAs are monitored and regulated,” said Mark B. Taubman, M.D., dean of the University of Rochester School of Medicine and Dentistry. “Her dedication to her science and to the field of RNA biology has opened the door to the development of RNA-based therapeutics for a wide range of disorders that you can’t reach with conventional drugs. We’re thrilled that her contributions are being recognized with this prestigious award.”
RNA secured its place in the public eye in 2020 with the development and approval of multiple mRNA COVID-19 vaccines. Years of research by Maquat, Steitz and Krainer helped set the stage for the rapid development of these vaccines.
The J. Lowell Orbison Endowed Chair and Professor in the Department of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry, Maquat is the recipient of several other significant honors, including:
- Wiley Prize in Biomedical Sciences (2018)
- Vanderbilt Prize in Biomedical Science (2017)
- Canada Gairdner International Award (2015)
- RNA Society’s Lifetime Achievement Awards in Service (2010) and in Science (2017)
- Election to the National Academy of Medicine (2017), the National Academies of Sciences (2011) and the American Academy of Arts and Sciences (2006) More about Nonsense-Mediated mRNA Decay
Winners of the Wolf Prize are selected annually by an international jury committee of the Wolf Foundation; prizes are awarded regardless of religion, gender, race, geographical region, or political view. The official announcement of this year’s prize by the President of the State of Israel, Reuven Rivlin, was made on February 9, 2021.
More about Nonsense-Mediated mRNA Decay
Disease: Gene expression gone awry.
The central dogma of biology is that genetic instructions in DNA are transcribed into messenger RNAs (mRNAs) that deliver the instructions to ribosomes, which then translate that information into the proteins that carry out myriad functions throughout the body. The production of mRNA is a crucial component of gene expression.
Disease is gene expression gone awry, and Maquat helped elucidate one of the most important and incredibly complex aspects of gene expression: quality control.
Mistakes in cells happen all the time. Humans have 20,000 protein-coding genes but are able to produce many more than 20,000 proteins through alternative pre-mRNA splicing. A single gene can generate multiple proteins by encoding a pre-mRNA from which various exons (including protein-coding regions) can be mixed and matched (alternatively spliced). This ability to diversify greatly increases the margin of error, but fortunately, the human body has built-in systems, like NMD, to eliminate potentially harmful slip-ups.
Stop Signals: Flaws in gene expression.
One common flaw in gene expression is the introduction of an early “stop” signal. Normally, this stop signal (termination codon) appears at the end of the genetic instructions in mRNA for protein synthesis to indicate that the instructions have been read start-to-finish and that all of the information has been translated into a full-length, functional protein.
Early stop signals, called “premature termination codons” or “nonsense codons,” prevent the genetic instructions in mRNA from being read completely. Consequently, protein synthesis is cut short, resulting in an incomplete or truncated protein that doesn’t function normally, and worse, could be toxic. Similar to installing a sink with only half of the instructions, or baking a cake with half of a recipe, premature termination codons lead to undesired, and oftentimes dire, results in a cell.
Maquat defined the mechanism that helps cells detect the difference between a premature stop signal and a normal stop signal. Her studies revealed how NMD works to identify and eliminate mRNAs containing premature termination codons and thereby prevent production of truncated proteins.
Maquat also identified the molecular “players,” and the routes and patterns they need to follow, for NMD to work properly. Among her most noteworthy contributions is her discovery of the exon-junction complex (EJC), a splicing-dependent “mark” that tags an mRNA so the cell can define which termination codons are premature and should trigger NMD. She defined the 50-55-nucleotide rule, which determines which mRNAs containing premature termination codons are subject to degradation by NMD. She also discovered the “pioneer round of translation,” during which NMD occurs.
NMD: The power to help, and harm.
Throughout her 40-year career, Maquat found that while nonsense-mediated mRNA decay evolved to shield humans from innate mistakes, it has the power to cause harm, too.
Inherited and acquired mutations can also introduce premature termination codons. In fact, one-third of all genetic disorders are caused by mutations that result in a premature termination codon. Many individuals with beta0 thalassemia have a nonsense mutation that introduces a premature termination codon in the gene encoding the beta-globin protein. The premature termination codon springs the NMD machinery into action and the mRNA transcript for beta-globin protein is destroyed. No beta-globin protein is produced and patients can’t make hemoglobin.
Some individuals with cystic fibrosis are similar. A nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to a premature termination codon and NMD follows. The CFTR protein, which is responsible for regulating the flow of salt and fluids in and out of cells, is defective or isn’t made. The result is the buildup of thick mucus and persistent lung infections that characterize cystic fibrosis.
In both of these cases, if you could override or stop NMD—for example, by efficiently suppressing the nonsense codon—normal, healthy proteins would be made and individuals wouldn’t be sick. Thanks to 40 years of research by Maquat and others, scientists are beginning to put the mechanistic findings related to NMD to use to design treatments.
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