Abstract

Decapping is a central step in mRNA decay. The Dcp2 decapping complex is conserved throughout eukaryotes and is a key component of processing bodies (PBs), cytoplasmic granules of repressed messenger ribonucleoproteins (mRNPs). The mechanism by which mRNPs are modulated to allow decapping by the Dcp2 decapping complex is poorly understood. The objective of this proposal is to gain insights into how mRNPs are modified and remodeled in preparation for decapping, by addressing the following questions: 1) what is the role of the C-terminal RGG domain of the Lsm4 component of the Lsm1-7 complex in decapping and PB formation, 2) How does the Dcp2 decapping complex remodel the eIF4F cap-binding complex to gain access to the mRNA cap, and 3) what is the role of mRNA tailing in decapping and decay of endonucleolytically cleaved mRNA? Pursuing these questions should provide new insights into the mechanisms by which the Dcp2 decapping complex targets mRNAs for decapping and decay. This should provide new fundamental insights into the role of mRNP modification and remodeling in mRNA regulation. Relevance to Public Health The control of mRNA turnover is critical for proper regulation of gene expression, and its misregulation has been identified as a cause or a consequence of multiple human disorders. The studies described here are aimed at understanding the mechanisms by which mRNAs in human cells are modified and remodeled in preparation for decapping, a central step in mRNA turnover. This should provide fundamental new insights into mechanisms of mRNA regulation, which when deregulated can lead to disease.

Public Health Relevance

mRNA degradation plays an important role in regulation of gene expression, the mis-regulation of which has been linked to multiple human disorders. mRNA decapping is a critical step in mRNA degradation;yet the mechanisms by which the mRNA decapping machineries are activated on target mRNAs remain poorly understood. The goal of this proposal is understand how human mRNA-protein complexes are modified and remodeled to allow activation of the Dcp2 decapping machinery.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077243-06
Application #
8694051
Study Section
Special Emphasis Panel (ZRG1-GGG-L (02))
Program Officer
Bender, Michael T
Project Start
2007-08-13
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$285,808
Indirect Cost
$95,808

  Institution

Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464
Arribas-Layton, Marcos; Dennis, Jaclyn; Bennett, Eric J et al. (2016) The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation. Mol Cell Biol 36:2226-35
Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189
Fu, Rui; Olsen, Myanna T; Webb, Kristofor et al. (2016) Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. RNA 22:373-82
Wang, Ying; Arribas-Layton, Marc; Chen, Yifang et al. (2015) DDX6 Orchestrates Mammalian Progenitor Function through the mRNA Degradation and Translation Pathways. Mol Cell 60:118-30
Erickson, Stacy L; Corpuz, Elizabeth O; Maloy, Jeffrey P et al. (2015) Competition between Decapping Complex Formation and Ubiquitin-Mediated Proteasomal Degradation Controls Human Dcp2 Decapping Activity. Mol Cell Biol 35:2144-53
Hausburg, Melissa A; Doles, Jason D; Clement, Sandra L et al. (2015) Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. Elife 4:e03390
Reznik, Boris; Clement, Sandra L; Lykke-Andersen, Jens (2014) hnRNP F complexes with tristetraprolin and stimulates ARE-mRNA decay. PLoS One 9:e100992
Arribas-Layton, Marcos; Wu, Donghui; Lykke-Andersen, Jens et al. (2013) Structural and functional control of the eukaryotic mRNA decapping machinery. Biochim Biophys Acta 1829:580-9
Erickson, Stacy L; Lykke-Andersen, Jens (2011) Cytoplasmic mRNP granules at a glance. J Cell Sci 124:293-7

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