Researchers discover critical detail of cellular defense against genetic mistakes

Researchers are closing in on a completed diagram of how human cells protect themselves against constant genetic mistakes that contribute to most diseases, according to a study to be published in the April 18 edition of the journal Cell.

The blueprint for the human body is encoded in genes. Gene expression is the process by which those blueprints are converted into proteins that make up the body’s structures and send its signals. When molecular biologists began analyzing the complete set of human genes (the human genome) in 2001, one surprise was that humans have as few as 30,000 genes when, given their complexity, they should have more than 100,000. How can humans have one-fifth as much genetic material as wheat, for instance, or share one quarter of their genes with fish?

One answer is that humans do more with fewer genes. While genes consist of chains of deoxyribonucleic acids (DNA), they are put into practice by chains of ribonucleic acid chains (RNA), which are modified copies of DNA. Messenger RNA (mRNA) is transported to cellular factories called ribosomes that receive instructions for building proteins by “reading” mRNA templates, a process called translation. Remarkably, about 75 percent of human genes code for more than one protein through a process called alternate RNA splicing. Unfortunately, the more intricate the splicing process, the greater the opportunity for error. More than one-third of alternatively spliced mRNAs are flawed, and must be destroyed before they can cause harm. Thus, cellular processes that detect and eliminate processing errors are vitally important to effective gene expression.

In recent years, researchers at the University of Rochester Medical Center have revealed the existence of a natural surveillance system called nonsense-mediated mRNA decay (NMD) that determines which mRNAs are fit to serve as protein templates and sees to the destruction of those with flaws. Researchers hope to tweak the process such that it catches more genetic errors in some cases, or leaves more templates for helpful proteins in place in others, based on the disease at hand. To do so will require a highly detailed knowledge of the NMD pathway.

“The current results uncover a critical and previously unappreciated step during the natural process that finds flaws in mRNAs,” said Lynne E. Maquat, Ph.D., J. Lowell Orbison Endowed Chair and professor of Biochemistry & Biophysics at University of Rochester Medical Center, director of the University of Rochester Center for RNA Biology and lead author of the Cell piece. “This work has important implications for our understanding of how one of the human cell’s most important activities, protein synthesis, undergoes quality control.”