The control of mRNA stability is a critical determinant in the post-transcriptional regulation of eukaryotic gene expression. Changes in mRNA stability can have profound consequences and may manifest as clinical phenotypes. This is perhaps best illustrated by the ability of aberrantly expressed proto-oncogenes that can give rise to malignancies and by the imbalanced 1 and 2 globin gene expression resulting in thalassemias. Despite the importance of mRNA stability in the control of gene expression, progress has only recently been made in the identification and characterization of the components that control mRNA turnover. We have focused our efforts on the study of nucleases and the pathways involved in mRNA decay in mammals, in particular, the two decapping enzymes, Dcp2 and DcpS. Dcp2 is the mRNA decapping enzyme that functions on capped mRNA while DcpS functions as the clearinghouse to hydrolyze the resulting cap structure following 34 to 54 decay of an mRNA. The long-term objective of this proposal is to understand the mechanisms that regulate mRNA decapping and mRNA decay in mammals and to utilize this information to control gene expression under normal and disease states. We have shown that Dcp2 is a transcript-specific decapping protein that is not uniformly expressed and is even undetectable in certain tissues indicating that there are as yet unknown decapping enzymes in mammals. We have also identified a protein implicated in X-linked mental retardation as a regulator of decapping. Furthermore, we have shown that DcpS is a modulator of the nuclear cap binding protein-mediated functions in addition to its role in mRNA turnover as well as the target substrate of a drug candidate for the treatment of spinal muscular atrophy. In this proposal, i) we will test the impact of Dcp2 and its absence on mRNA decay and identify the non-Dcp2 mRNA decapping enzyme in mammalian cells in Aim I;ii) characterize the mechanism by which the decapping regulator influences mRNA stability in Aim 2;and iii) assess the modulatory role of DcpS on cytoplasmic functions including mRNA stability and translation in Aim 3. This work will provide insights into a fundamental mechanism involved in the post-transcriptional control of gene expression and will provide a framework for novel approaches for therapeutic intervention in human disorders.

Public Health Relevance

Our overall objective is to understand the precise controls involved in mRNA turnover and to utilize this information to regulate gene expression under normal and disease states. Decapping is a key step in the stability and ultimate demise of an mRNA. We will build on our ongoing functional studies of the Dcp2 and DcpS decapping enzymes in mammalian gene expression and their correlation to both mental retardation and spinal muscular atrophy. We will determine the impact of the presence, and surprising natural absence, of Dcp2 in mRNA decay, its regulation and the modulatory function of DcpS on cytoplasmic cap-binding protein processes. This work will provide insight into a fundamental mechanism involved in the post-transcriptional control of gene expression and could provide a framework in novel approaches for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067005-08
Application #
8305785
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
2004-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$321,779
Indirect Cost
$113,508
Name
Rutgers University
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Jiao, Xinfu; Chang, Jeong Ho; Kilic, Turgay et al. (2013) A mammalian pre-mRNA 5' end capping quality control mechanism and an unexpected link of capping to pre-mRNA processing. Mol Cell 50:104-15
Li, You; Dai, Jihong; Song, Mangen et al. (2012) Dcp2 decapping protein modulates mRNA stability of the critical interferon regulatory factor (IRF) IRF-7. Mol Cell Biol 32:1164-72
Li, You; Song, Mangen; Kiledjian, Megerditch (2011) Differential utilization of decapping enzymes in mammalian mRNA decay pathways. RNA 17:419-28
Jiao, Xinfu; Xiang, Song; Oh, Chanseok et al. (2010) Identification of a quality-control mechanism for mRNA 5'-end capping. Nature 467:608-11
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Jiao, Xinfu; Chen, Hongxin; Chen, Jianmin et al. (2009) Modulation of neuritogenesis by a protein implicated in X-linked mental retardation. J Neurosci 29:12419-27

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