Researchers Find a Eukaryotic mRNA Policing System

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important peer-reviewed papers within a range of research fields, based on the recommendations of a faculty of more than 1,400 leading researchers. Each issue, The Scientist publishes a review, like the one above, that examines related papers in a single field. We also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information visit www.facultyof1000.com. Genes might grab headlines, and proteins might do the actual work of cells, but without messenger RNA (mRNA) both of them would be powerless. mRNA is the key intermediary in gene expression, translating the DNA's genetic code into the amino acids that make up proteins. But critical as mRNAs are, cells have reasons to destroy them. For example, cells sometimes make errors when producing mRNAs and they need ways to purge the aberrant messages. "The whole process, like many biological reactions, is a balance in terms of how fast you can do it, and how many mistakes you can make; just like a normal factory," explains Roy Parker, associate investigator, department of molecular and cellular biology and biochemistry and molecular biophysics, University of Arizona, and an author on two papers recently highlighted by F1000.1,2 "So, if you look at the whole process of making and using mRNAs, there are lots of ways the cell recognizes and degrades mistakes.... The cell has quality control," he says. Nonsense-mediated decay (NMD) is one well-studied eukaryotic mRNA decay mechanism that eliminates mRNAs with premature termination codons; without NMD, cells would produce truncated proteins. Parker, along with Harry Dietz, professor at Johns Hopkins' Institute for Genetic Medicine, discovered an additional eukaryotic mRNA-policing system, called nonstop decay, which eliminates those mRNAs lacking termination codons. "It has been known for quite some time in bacteria that cells are able to degrade proteins [which] are the product of mRNAs that lack termination codons," says Lynne Maquat, professor of biochemistry and biophysics, University of Rochester, who reviewed these papers for Science3 and the Faculty of 1000. "These two labs have worked together to discover that a comparable pathway exists in yeast and mammalian cells." Although the existence of such a pathway in eukaryotes may not be surprising, the mechanism by which it functions is. In yeast, it is known that polyA tail-binding proteins are necessary to protect a structure known as the 5' cap. Normally, when mRNAs are degraded, the polyA tail is removed, causing the loss of these protective polyA-binding proteins. Thus, the 5' end is decapped and an exonuclease begins the process of mRNA degradation in the 5' to 3' direction. According to Parker, the researchers anticipated that if a ribosome ran to the end of the message, it might bump off the protective proteins on the polyA tail, exposing the decapping enzyme that would kill the RNA. Instead, the Parker and Dietz groups discovered that these nonstop mRNAs are degraded by the exosome, a highly conserved complex of 3' to 5' exonucleases that are known to process and degrade the RNAs and an adaptor protein. "The fact that it was the exosome and an adaptor protein [called Ski7p] was something of a surprise," says Parker. "The paper from the Dietz lab1 does a survey of genes that are either known to produce cDNAs that don't seem to have a termination codon in them, or they've looked at coding regions that seem to have a polyA signal in them," says Maquat. Adds Parker, "One of the surprises to me from this whole thing is if you look at the EST [Expressed Sequence Tags] libraries from yeast, in 1% of the clones you see polyA sites within coding regions that could create these nonstop RNAs, which are very unstable. At steady state, they would be rare, but at any given time probably 10% or more of transcripts are having the polyA tail put on in the wrong place." The presence of these transcripts, says Maquat, justifies the need for degradation of nonstop mRNAs. Although NMD and nonstop decay work through different mechanisms, Parker says he thinks that they could be manipulated in a complementary way to fight certain kinds of disease. "There is a lot of interest in nonsense-mediated decay because about a third of all human genetic diseases are nonsense codons. They prevent the protein from being made because the mRNA is destroyed by nonsense-mediated decay," he says. Drugs such as aminoglycosides have been developed that encourage ribosomes to read-through nonsense codons, so proteins can be made in diseases such as cystic fibrosis. However, according to Parker, these drugs do not work very well. He and Dietz speculate that one reason may be that the mRNAs resulting from drug-induced read-through are degraded by the nonstop decay mechanism. "Some percent of the time you're causing ribosomes to get all the way to the end and trigger nonstop decay. You would only need one ribosome to get to the end, read through all the nonstop codons, and reach the polyA tail," he says. However, if these read-through drugs could be combined with others that suppress nonstop mRNA decay, it could stabilize the messages and improve efficacy. Searching for such drugs is underway in the Dietz lab, Parker says. Other pursuits, says Maquat, include whether a protein that mimics tRNA is involved in the process (as is the case in bacteria), and whether a mechanism exists for degrading the protein products of mRNAs lacking termination codons. Mignon Fogarty (mignon@welltopia.com)is a freelance writer in Santa Cruz, Calif. References 1.P.A. Frischmeyer et al., "An mRNA surveillance mechanism that eliminates transcripts lacking termination codons," Science, 295:2258-61. March 22, 2002. 2.A. van Hoof et al., "Exosome-mediated recognition and degradation of mRNAs lacking a termination codon," Science, 295:2262-4. March 22, 2002.

Researchers Find a Eukaryotic mRNA Policing System

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