New research describes a mechanism by which an essential quality control system in cells identifies and destroys faulty genetic material. The findings were published in Nature Communications.
The study provided evidence for direct communication between the cell's protein synthesis machinery - the ribosome - and the protein complex that recognizes and destroys defective genetic intermediates called messenger RNAs (mRNAs).
Cells convert sections of DNA encoding genes into mRNA that serves as a blueprint for the synthesis of a protein. In some cases, the DNA template has suffered damage or errors occur when copying the information such that the mRNA contains a "premature stop codon." Premature stop codons cause the ribosome to halt synthesis early, before the entire protein is made, resulting in a truncated protein that often lacks function, or worse, can wreak havoc on other normal processes in the cell. The research focused on how cells identify when an mRNA has a premature stop codon and then target the faulty genetic intermediate for rapid disposal to avoid the harmful effects of truncated proteins.
In the new study, researchers uncovered that ribosomes were stalled on mRNA at premature stop codons. This observation led to the discovery that one of proteins in the surveillance complex, UPF1, was important for interacting with the stalled ribosome and assisting with its release from the mRNA.
The inability of UPF1 to properly communicate with the ribosome results in the failure of the mRNA to be targeted to rapid elimination and inactivates the whole surveillance system. Moreover, the findings indicated that UPF1 harnesses energy found in adenosine triphosphate (ATP)- a reserve for energy storage in the cell - to influence the function of the ribosome, and that this step in the cellular checkpoint is necessary for recognizing and destroying mRNA with premature stop codons.
"About one-third of all genetic diseases involve a gene mutation that introduces a premature stop codon into the corresponding mRNA. In some cases, a therapeutic strategy that either instructs the ribosome to bypass this stop or that interferes with the recognition or elimination of the mRNA could restore some level of functional protein and lessen disease symptoms in patients," said the senior author. "What is most exciting is that once developed, such a strategy could be applied not just to a single genetic disease, but to any that occur as a consequence of these particular mutations."
http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=484
http://www.nature.com/articles/ncomms14021
Essential quality control system in cells identifies and destroys faulty genetic material
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