COLUMBUS, Ohio – Scientists have found that living cells will sometimes "shoot the messenger" as a way to halt production of certain proteins.
The study, published in the May 21 issue of the journal Molecular Cell, shows that cells sometimes destroy the chemical messages that contain information for making proteins even as the messages are being "read." The work was done by scientists at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
The findings describe a poorly understood biochemical mechanism that cells may use to suddenly stop producing proteins like growth factors that activate genes in response to a hormone or other signaling chemical. The mechanism also plays a key role in Cooley's anemia, which causes the loss of red blood cells in infants and children, and may contribute to changes in gene activation in cancer.
The mechanism involves a recently discovered enzyme that destroys the ribbon-like molecules of messenger RNA (mRNA). Messenger RNA is a copy of gene, and it contains information that describes the structure of a protein. It carries that information from genes in the cell nucleus to the region of the cell where proteins are made.
"Controlling mRNA degradation is one of the key ways that cells regulate how much of a particular protein they produce," says senior author Daniel R. Schoenberg, professor of molecular and cellular biochemistry. "The mechanism we describe is a completely new concept in the field."
Proteins carry out most of the work in cells. Production of a protein begins when the gene carrying the information for a protein opens -- the DNA unwinds -- and the information is copied in the form of another molecule, mRNA.
Next, the mRNA leaves the cell nucleus and enters the cell cytoplasm. There, complexes known as ribosomes attach to one end of the mRNA.
The ribosomes then travel along the mRNA, reading the encoded genetic message as they go. That message describes the chain of amino acids needed to make that particular protein.
As each ribosome travels along the mRNA, it builds the protein by joining the next amino acid in the sequence. When it reaches the end, it releases the raw protein into the cytoplasm.
After making a protein, the mRNA is either reused to make more of its encoded protein, or it is destroyed. Scientists generally believe the mRNA destruction is carried out in multiple steps, beginning when one end of the mRNA is lopped off. The doomed molecule is then transported to nearby recycling complexes.
The current study, carried out by Feng Yang, a graduate student in the Ohio State Biochemistry Program, shows that some mRNAs are degraded through a quicker means: they are hit much earlier in the process.
The findings show that an enzyme Schoenberg previously discovered, known as PMR1 (polysomal ribonuclease 1), attaches to the mRNA of some proteins and chops the mRNA into pieces while ribosomes are reading it.
"The enzyme is sitting right there waiting to nail it, poised for someone to pull the pin on the hand grenade," Schoenberg says. "That gives the cell tremendous flexibility when an mRNA needs to be degraded."
This pathway works only on certain classes of mRNA, and Schoenberg now wants to learn how the enzyme identifies which mRNA molecules to join to, and to identify the signals that trigger PMR1 to destroy an mRNA.
A grant from the National Institutes of Health funded this research.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute encompasses six interdisciplinary research programs, over 200 investigators and the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. The OSU CCC-James is a founding member of the National Comprehensive Cancer Network, and The James is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.
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