UT Scientists Challenge RNA Quality Control Model
HOUSTON—(March 12, 2008)—DNA biologists may have to go back to the drawing board when it comes to explaining the body’s ability to detect errors during the translation of genetic information into proteins.
A popular RNA quality control model collapsed during a yeast study by UT Houston’s Ambro van Hoof, Ph.D., and Stacie Meaux.
Recently, Ambro van Hoof, Ph.D., and Stacie Meaux, both with The University of Texas Health Science Center at Houston, and Kristian Baker, Ph.D., of Case Western Reserve University, refuted a popular quality control model involving premature termination codons (PTCs), which affect one in three patients with genetic disorders.
“The Human Genome is like a big library and this library needs to be copied into Ribonucleic Acid (RNA) much like a Xerox machine copies books into more manageable and useful documents,” said van Hoof, assistant professor of microbiology and molecular genetics at The University of Texas Medical School at Houston. “There are good copies and bad copies, and your body can tell the difference.”
RNA contains three letter words called codons, which when strung together in the proper order create the amino acids necessary for proteins. Some of these three letter words do not signal an amino acid, but signal the cell to stop making this protein “With a premature stop codon, you end up with the wrong protein, but also not enough of the protein,” van Hoof said.
For years, the faux 3’ UTR (Untranslated Region) model has been used to describe the body’s capacity to identify and destroy RNAs with premature termination codons, which can short-circuit the translation of genetic information into proteins and can lead to health problems. According to the model, the proximity of stop codons to a string of genetic letters called a Poly(A) Tail and/or a protein called PAB1 impacts the body’s ability to differentiate between premature stop codons and normal stop codons.
“Our results established that neither the Poly(A) Tail nor PAB1 is required for the discrimination of premature termination codons from normal termination codons. We used yeast because it allows us to do many experiments very easily, and the same should be true for humans,” van Hoof said.
The study in the Jan. 18 issue of “Molecular Cell” was titled “Nonsense-Mediated mRNA Decay in Yeast Does Not Require PAB1 or a Poly(A) Tail.”
Samuel Kaplan, Ph.D., professor and chairman of the Department of Microbiology and Molecular Genetics at the UT Medical School at Houston, said, "The ability of living cells to discriminate and thus to dispense with ‘junk’ or prematurely processed proteins because of a defect in the informational mRNA due to the presence of a nonsense code word is critical to the proper handling of the informational content of the DNA code, and the work of Dr. van Hoof and Ms. Meaux helps us better understand this process, and with it the development of proper therapeutics."
Premature termination codons are responsible for 15 percent of the cases of Duchenne muscular dystrophy and 10 percent of cystic fibrosis, according to PTC Therapeutics, a biopharmaceutical company which has catalogued 1,800 distinct genetic disorders linked to premature termination codons. The firm recently began clinical trials on an oral medication to treat conditions related to premature termination codons.
"The discovery by Ambro's group is going to open up a new avenue for developing therapeutic agents to modulate nonsense-mediated mRNA decay, thus alleviating the negative impact of those genetic disorders by stopping cells from making aberrant truncated proteins," said Ann-Bin Shyu, Ph.D., professor and Jesse H. Jones Chair in Molecular Biology at the UT Medical School at Houston. Shyu’s lab has been studying mRNA decay pathways including nonsense-mediated mRNA decay in humans for two decades.
This research was supported by grants from the National Institutes of Health and the Pew Scholars Program to van Hoof and by Case Western Reserve University to Baker.