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Stop that Nonsense!

Flawed Molecular Coding Under Increasing Scrutiny by Scientists

Friday, September 06, 2002

There’s little room for nonsense in medicine. Stopping even just a little molecular nonsense would open up new vistas for pharmaceutical companies and could help alleviate many types of disease, say scientists at the University of Rochester Medical Center who are building their reputation on understanding how cells deal with “nonsense.”

Scientists use the term to refer to flawed molecular coding that results in abnormally shortened proteins and could cause harm. The flaw is oftentimes a mistake in either the genetic material, DNA, or its product, RNA, which encodes instructions for making proteins. The body’s strict molecular quality-control system usually weeds out the mistakes before they can churn out proteins – but the full-length versions of those proteins are often vital for health. It’s like a sharp-eyed editor who immediately tosses out the draft for a good book simply because the author misspelled a word early on.

Scientists estimate that nearly one-third of inherited disorders result from such mistakes, which are eliminated by dogmatic quality control. But if the body could be trained to overlook some of these mistakes and allow for what is called ‘nonsense suppression,” it could produce adequate amounts of the full-length proteins, whose absence causes diseases like cystic fibrosis and contributes to many forms of cancer.

The Rochester researchers are focusing their sights on this quality-control system, known as nonsense-mediated decay (NMD). In a recent paper in the EMBO Journal published by the European Molecular Biology Organization, a team led by Lynne Maquat, Ph.D., professor in the Department of Biochemistry and Biophysics, identified several proteins that are central to the process.

Proteins are the workhorses that actually perform the molecular tasks which keep our bodies going day to day. While the Human Genome Project has focused attention on our DNA, that material is useful mainly because it calls for the production of specific proteins. It’s the job of a molecule known as messenger RNA, or mRNA, to take the instructions from DNA and direct the steps necessary to build proteins. mRNA molecules are like messengers in a factory, taking a blueprint and then heading to the floor and gathering a team to get the job done.

Sometimes, though, the mRNA doesn’t quite get the message right. One common error happens when an mRNA molecule harbors a “stop” or “nonsense” signal before a protein has been completely made.

Enter the body’s quality-control system. More than 20 years ago while studying a particular type of anemia called beta-thalassemia, Maquat discovered that the disease occurs because enzymes degrade mRNA molecules with errant “stop” signals, rather than allow them to continue on to make truncated proteins.

Last year Maquat published a paper in the journal Cell where she announced that nonsense-mediated decay targets what scientists call a “pioneer round of translation,” during which the body actually produces a kind of rough draft of a protein before giving the go-ahead to the mRNA molecule to begin mass production. In the recent EMBO paper, Maquat and colleagues identify several of the proteins that take part in this pioneer round and show that the mRNA puts together an extensive tool kit of molecular machinery to evaluate whether it should pass muster as a legitimate template for proteins. T

he identification of such “tool kits,” groups of molecules working together to achieve a task, keeps hundreds of lab groups like Maquat’s around the world constantly busy. Far from the simple and bland “DNA to RNA to protein” sequence of events that many people learn in high school, nearly every cell in the body embodies an incredibly complex construction site where tens of thousands of proteins work in tandem, snipping and cleaving molecules, removing “introns” and splicing together “exons” in various combinations, recruiting molecules to the site, and ferrying molecules over to ribosomes for assembly into proteins.

“There’s an incredible amount of activity in a small space,” says Maquat, who is secretary/treasurer of the RNA Society and who organized a meeting this summer on the topic of mRNA decay for the Federation of American Societies for Experimental Biology.

 “A single gene can result in many different proteins depending on how its encoded precursor mRNA is processed; we now know that more than half of human genes can make more than one protein. But with this wonderful flexibility often comes mistakes. The situation is turning out to be more complex than anyone ever dreamed. The degree of RNA processing that the cell undertakes is truly amazing.”

The idea of trying to bypass the body’s mRNA surveillance system is formidable. Maquat notes that the system is necessary for survival, and that without it, bad mRNA would create even more instances of disease. “mRNAs that prematurely terminate protein synthesis are made all the time, and the body needs some way to eliminate them,” she says. Nevertheless, targeted bypassing of the NMD system would offer a new approach for treating nearly one-third of inherited disorders.

Working on the project with Maquat were post-doctoral fellow Fabrice Lejeune, Ph.D.; former research associates Yasuhito Ishigaki, Ph.D., now at Kanazawa University in Japan, and Guillaume Serin, Ph.D., now at a biotech firm, Oncodesign, in France; and technician Xiaojie Li. The research was funded by the National Institute of General Medical Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.

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