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Topic Name: Case Researchers Argue “faux 3’ UTR” Model could not Explain how Cells Recognize and Destroy Deviant mRNA

Category: Genetic Engineering

Research persons: Kristian E. Baker, Ph.D., Ambro van Hoof, Ph.D.

Location: Case Western Reserve University School of Medicine, United States

Details

In the January 18th issue of Molecular Cell, Case Western Reserve University School of Medicine researcher Kristian E. Baker, Ph.D. challenges molecular biology’s established body of evidence and widely-accepted model for nonsense-mediated messenger ribonucleic acid (mRNA) decay. With her collaborator, Ambro van Hoof, Ph.D. of The University of Texas Health Sciences Center, Baker directly tested the “faux 3’ UTR” model and proved it could not explain how cells recognize and destroy deviant mRNA. This landmark discovery will redirect mRNA research and expand opportunities for new discoveries in understanding the cells’ ability to protect itself from these potential errors.

In all cells, including human, mRNA is a copy of the information carried by a gene on the DNA. Occasionally, mRNA contains errors that can make the information it carries unusable. Cells posses a remarkable mechanism to detect these aberrant mRNAs and eliminate them from the cell – this process represents a very important quality control system for gene expression. “A significant amount of past research in this area of RNA biology has collected data to support the ‘faux 3’ UTR’ model for mRNA quality control, and, as a result, has shaped present research directions in the field,” said Baker. “Our recent findings preclude this explanation and will, undoubtedly, result in a rethinking by many as to how to experimentally approach this important cellular process.”

For decades researchers have been puzzled by cells’ ability to differentiate between “normal” mRNA and those carrying certain types of mutations. mRNA transports DNA’s genetic coding information to the sites of protein synthesis: ribosomes. Cells are able to identify mRNA carrying a mutation and prevent it from reaching the protein synthesis phase. Once identified, the cell destroys the abnormal, mutated mRNA. This naturally occurring process ensures malfunctioning proteins are not produced. Using a yeast model system, Baker’s research offers a better understanding of this mRNA quality control process which closely mimics the process in human cells.

Baker’s research on nonsense-mediated mRNA decay not only provides an advanced understanding of an important process in the regulation of gene expression, but may help lead to new therapeutic strategies in the treatment of genetic diseases. Many inherited conditions, including cystic fibrosis, are a consequence of mutations resulting in the recognition of non-functional mRNA and the subsequent elimination by nonsense-mediated mRNA decay. Because cells eliminate the abnormal mRNA, no protein is produced. With genetic diseases, researchers are hypothesizing it might be beneficial for the cell to express the protein, even though it is not completely functional. The rational is it will be better for these patients to have protein of some function rather than no protein at all. Cystic fibrosis clinical trials are currently underway with a goal of producing the partially functional proteins, before the cell’s natural elimination process takes place. Using Baker’s findings, researchers will have a better understanding of how to modulate the recognition of the abnormal mRNAs as to allow the mRNA to remain in the cell and produce the protein.

“This finding is an important step in advancing our understanding of mRNA function,” said Baker. “In addition, it emphasizes the important link between basic and clinical science; the more we understand the basic biological processes that are underway in the cell, the better equipped we are to directly address clinical therapies.”

Note for mRNA
Messenger ribonucleic acid (mRNA) is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein. In mRNA as in DNA, genetic information is encoded in the sequence of four nucleotides arranged into codons of three bases each. Each codon encodes for a specific amino acid, except the stop codons that terminate protein synthesis. This process requires two other types of RNA: transfer RNA (tRNA) mediates recognition of the codon and provides the corresponding amino acid, while ribosomal RNA (rRNA) is the central component of the ribosome's protein manufacturing machinery.
The brief life of an mRNA molecule begins with transcription and ultimately ends in degradation. During its life, an mRNA molecule may also be processed, edited, and transported prior to translation. Eukaryotic mRNA molecules often require extensive processing and transport, while prokaryotic molecules do not.

Note for Ribosome
Ribosomes are complexes of RNA and protein that are found in all cells. Prokaryotic ribosomes from archaea and bacteria are smaller than most of the ribosomes from eukaryotes such as plants and animals. However, the ribosomes in the mitochondrion of eukaryotic cells resemble those in bacteria, reflecting the evolutionary origin of this organelle.
The function of ribosomes is the assembly of proteins, in a process called translation. Ribosomes do this by catalysing the assembly of individual amino acids into polypeptide chains; this involves binding a messenger RNA and then using this as a template to join together the correct sequence of amino acids. This reaction uses adapters called transfer RNA molecules, which read the sequence of the messenger RNA and are attached to the amino acids.
Ribosomes are about 20nm (200 Ångström) in diameter and are composed of 65% ribosomal RNA and 35% ribosomal proteins (known as a Ribonucleoprotein or RNP). They translate messenger RNA (mRNA) to build polypeptide chains (e.g., proteins) using amino acids delivered by transfer RNA (tRNA). Their active sites are made of RNA, so ribosomes are now classified as "ribozymes".

Note for Protein Synthesis
Protein biosynthesis (synthesis) is the process in which cells build proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription which are then used for translation. Protein biosynthesis, although very similar, differs between prokaryotes and eukaryotes.
Transcription is the process by which an mRNA template, encoding the sequence of the protein in the form of a trinucleotide code, is transcribed from the genome to provide a template for translation. Transcription copies the template from one strand of the DNA double helix, called the template strand.
Protein translation involves the transfer of information from the mRNA into a peptide, composed of amino acids. This process is mediated by the ribosome, with the adaptation of the RNA sequence into amino acids mediated by transfer RNA. Numerous initation and elongation factors also play a role.

Note for Cystic fibrosis
Cystic fibrosis (CF) is a hereditary disease that affects mainly the lungs and digestive system, causing progressive disability, and, in most cases, early death. Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply cystic fibrosis. Average life expectancy is around 36.8 years, although improvements in treatments mean a baby born today could expect to live longer.
Difficulty breathing and insufficient enzyme production in the pancreas are the most common symptoms. Thick mucus production, as well as a less competent immune system, results in frequent lung infections, which are treated, though not always cured, by oral and intravenous antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and potential infertility (mostly in males, due to the condition Congenital bilateral absence of the vas deferens) result from the effects of CF on other parts of the body. Often, symptoms of CF appear in infancy and childhood; these include meconium ileus, failure to thrive, and recurrent lung infections.
Cystic fibrosis is one of the most common life-shortening, childhood-onset inherited diseases. In the United States, 1 in 3900 children is born with CF. It is most common among Europeans and Ashkenazi Jews; one in twenty-two people of European descent carry one gene for CF, making it the most common genetic disease among such people.