Inhibition of nonsense-mediated mRNA decay by translational readthrough

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NHLBI	MOLBIO-1

Authors

• S.L. Baker
• J.R. Hogg

Abstract

The nonsense-mediated mRNA decay (NMD) pathway plays an important role in modulating the severity of many genetic diseases by recognizing and degrading mRNAs containing premature termination codons. The selective decay of aberrant mRNAs is carried out by the RNA helicase Upf1 and several additional NMD factors. We have previously found that inefficient translational readthrough permits Upf1 binding to mRNPs but inhibits degradation of mRNAs. These findings point to a model in which Upf1 accumulation in mRNPs is a prerequisite for decay but is not sufficient to induce transcript destruction. Instead, the initiation of decay requires the completion of one or more additional rate-limiting steps susceptible to disruption by translational readthrough events. We are currently investigating the mechanism by which rare translational readthrough events prevent commitment to RNA decay despite efficient recruitment of Upf1. As part of these studies, we have constructed a dual-fluorescent protein reporter that can be used to simultaneously assay mRNA decay, translational readthrough, and the protein composition of mRNPs. With this system, we are comparing the ability of distinct readthrough-promoting elements to inhibit NMD and analyzing the effects of readthrough on recruitment of Upf1 and other NMD proteins to mRNPs.

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