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Study provides insight into cellular defenses against genetic mutation

sized, a 7-methylguanosine cap is attached to the 5-prime end and a tail of repeating adenosine molecules to the 3-prime end. The cap and the tail protect the mRNA from enzymes that would otherwise destroy it from both ends.

Along with its protective role, the 5-prime cap is designed to bind to a complex of two linked cap-binding proteins (CBPs), CBP80 and CBP20. The cap-binding complex is part of the larger pioneer translation initiation complex, which enables mRNAs to be read by ribosomes during quality control review. Previous studies in the Maquat lab revealed two vital facts about cap-binding proteins. First, any mRNA with a CBP80 attached to its 5-prime cap can be translated by ribosomes. Secondly, mRNAs linked to CBP80 are targeted for NMD when a ribosome finds an early stop codon. Most recently, the Nature paper demonstrated for the first time that CBP80 works by activating a protein factor known to drive NMD called human up-frameshift (hUpf) protein 1.

A Matter of Spacing

Immature mRNA is made of both "must-read" pieces of RNA called exons that code for the building of proteins, and pieces called introns that do not code for proteins. For mRNA to mature, it must be cut and pasted by cellular machines that re-assemble end to end only exons in the final template for protein construction. In recent years, Maquat's team has confirmed that complexes that identify early nonsense codons form at exon-exon junctions the places where each "must read" section is joined to the next in the mature chain.

What Maquat and colleagues are learning is that much of the regulatory action of NMD depends on the physical spacing of molecules in the RNA chain. If a stop reading signal occurs too far ahead of the final exon in the chain, as marked by an exon-exon junction complex (EJC), the cell concludes that the stop codon has mistakenly fallen in the middle of a set of instructions. Specifically, Medical Center researchers now believe a
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Source:University of Rochester Medical Center


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