Gruber Prize goes to discovery of NMD

Research of nonsense-mediated mRNA decay is genetic breakthrough in fragile X

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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University of Rochester researcher Lynne E. Maquat, PhD, is co-recipient of this year’s Gruber Genetics Prize for her discovery of nonsense-mediated mRNA decay (NMD), a protein quality control system within cells.

Maquat and her team subsequently discovered that this control system is in overdrive in cells of people with fragile X syndrome — a discovery that represents a step forward in understanding how the disease develops and has helped guide treatment development.

Maquat, the founding director of the Center for RNA Biology at the University of Rochester, will share the Gruber Foundation’s $500,000 prize with Allan Jacobson, PhD, of the University of Massachusetts Chan Medical School, who described NMD’s mechanism in yeast.

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The Gruber Genetics Prize recognizes researchers from all over the globe who’ve done work in an area of genetics research that’s fresh enough to bring about important changes for people. Maquat and Jacobson will receive this year’s award on July 19 at the International Congress of Genetics in Melbourne, Australia.

“This award is a powerful recognition of Lynne’s amazing ability to discover, to innovate and to advance the boundaries of scientific knowledge,” Steve Dewhurst, PhD, said in a university press release.  Dewhurst is vice dean for research at the University of Rochester School of Medicine and Dentistry, in New York.

NMD is a quality control system that helps cells get rid of faulty messenger RNA (mRNA) molecules. mRNA is the intermediate molecule derived from DNA that serves as guide for protein production.

When there are mutations in the mRNA, the resulting proteins can be abnormal and potentially harmful to cells. NMD can spot these faulty mRNA molecules and break them down before they can be used to make proteins.

This system is important for maintaining the quality of proteins and for preventing the production of abnormal proteins that can cause disease. It also can help cells adjust and respond more quickly to changes in their environment to keep balance.

“The prize speaks to the fundamental importance of NMD as a biological process, and as a driver of both homeostasis [internal balance] and disease. This work will influence how we treat a range of inherited diseases, as well as many types of cancer, in the future,” Dewhurst said.

Maquat’s work showed that NMD is super-active in cells derived from fragile X patients. These cells lack FMRP, a protein that’s needed for normal brain development and whose deficiency can result in the range of symptoms seen in fragile X patients, from intellectual disability and delayed development to social and behavioral challenges.

Maquat’s team also showed that tuning down NMD using small molecules restored a number of functions that usually are lost in cells that lack FMRP.

Afuresertib blocked AKT enzyme

In a subsequent study, they also showed that when AKT — an enzyme that plays a key role in cell growth and survival — becomes overly active, as it does in fragile X, it turns on NMD. Using afuresertib, an experimental medicine under clinical testing for cancer, they blocked the activity of AKT and tamped down NMD.

“Lynne’s scientific prowess and steadfast commitment to her research is exemplary and has helped catapult the field of RNA biology to the forefront of medicine over the past decade,” said Mark B. Taubman, MD. Taubman is CEO of the University of Rochester Medical Center and dean of the School of Medicine and Dentistry.

“This is an exciting time, as Lynne and other scientists are putting her mechanistic findings related to NMD to use to design treatments,” Taubman added.

Besides being a professor of biochemistry and biophysics at the University of Rochester School of Medicine and Dentistry, Maquat holds appointments in pediatrics and in oncology and is the founding chair of Graduate Women in Science at the University of Rochester.