Organisms have evolved a number of molecular surveillance pathways to monitor and prevent cellular damage. One such system is the nonsense mediated decay (NMD) pathway. NMD functions to detect mRNAs with premature termination codons, such as occur in many inherited diseases, and target these mRNAs for rapid degradation and prevent the generation of truncated mutant proteins. However, NMD can exacerbate the effects of many inherited mutations: by targeting and degrading transcripts that otherwise would encode proteins with sufficient biochemical activity for normal function, the NMD pathway can essentially cause a complete loss of activity, and a subsequent disease. Thus inhibition of NMD has potential therapeutic benefit. However, NMD is an essential process in higher animals, including mammals, indicating the NMD pathway has important functions in normal cell biology. These functions are not well understood. Therefore, while NMD-inhibition therapies hold promise for treating certain genetic diseases, realizing this potential will require understanding the biological roles of NMD. To address this important question, we are using Drosophila to study the requirements for NMD during normal development and physiology. Specifically, we plan to determine whether NMD function is required in all tissues for organismal viability and identify the key targets mediating the biological roles of the NMD pathway in critical tissues. We are also using Drosophila to identify the cis-acting signals and trans-acting protein machinery that mediate NMD. We will identify cis-acting sequences directing endogenous targets for NMD-mediated degradation by combining microarray analysis of Drosophila NMD mutants with detailed bioinformatic analysis. To identify trans-acting components, we will use the genetic tools available in Drosophila to conduct efficient, large-scale genetic screens directed at identifying mutations that affect NMD. The screens are designed to identify novel components of the pathway, including those required for organismal viability. The screens will also identify new mutations in known NMD components, which will help define the molecular interactions among these components. Since the NMD pathway is conserved throughout evolution it is likely that the knowledge gained from these approaches will be applicable across a broad range of organisms, including humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084011-05
Application #
8225334
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
2008-05-05
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$265,509
Indirect Cost
$89,091
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Nelson, Jonathan O; Moore, Kristin A; Chapin, Alex et al. (2016) Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. Elife 5:
Chapin, Alex; Hu, Hao; Rynearson, Shawn G et al. (2014) In vivo determination of direct targets of the nonsense-mediated decay pathway in Drosophila. G3 (Bethesda) 4:485-96
Frizzell, Kimberly A; Rynearson, Shawn G; Metzstein, Mark M (2012) Drosophila mutants show NMD pathway activity is reduced, but not eliminated, in the absence of Smg6. RNA 18:1475-86
Long, A Ashleigh; Mahapatra, Cecon T; Woodruff 3rd, Elvin A et al. (2010) The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy. J Cell Sci 123:3303-15