This proposal focuses on the decapping and deadenylation of mRNA. Decapping is the removal of the 5'cap structure is an important step in the regulation of mRNA. The turnover of mRNA is intimately connected to the process of protein synthesis. Importantly, work from this grant has documented that factors involved in destroying mRNAs are themselves regulators of ribosome function. Specifically, a key component of the decapping complex called DHH1 slows ribosome translocation and this event serves to stimulate removal of the 5'cap and degradation of the transcript body.
The first Aim of this grant is designed to understand how DHH1 alters ribosome function. This proposal also focuses on deadenylation of mRNA. Deadenylation is the removal of the 3'poly(A) tail on an mRNA and required before mRNA decapping can occur.
Aim 2 of this grant focuses on understanding how deadenylation and decapping are coupled. Deadenylation is also thought to be the rate-limiting step in mRNA turnover. Importantly, deadenylation rates are variable between mRNA species but how these heterogeneity is achieved is unclear.
Aim 3 of this proposal is to determine how differential deadenylation rates occur. Together, these Aims highlight the importance of the decapping and deadenylase enzymes in controlling a diversity of gene expression events.

Public Health Relevance

Importance to Human Health RNA communicates the genetic information found within DNA. In order for cells to function appropriately, signals communicated by RNA must be turned on and off. This grant focuses on how RNA signals are turned off. Failure to regulate RNA appropriately has devastating cellular consequences that can lead to cancer, neurological defects, and embryological malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM080465-06A1
Application #
8506450
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Bender, Michael T
Project Start
2007-06-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$313,901
Indirect Cost
$109,915
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Alhusaini, Najwa; Coller, Jeff (2016) The deadenylase components Not2p, Not3p, and Not5p promote mRNA decapping. RNA 22:709-21
Chen, Ying-Hsin; Coller, Jeff (2016) A Universal Code for mRNA Stability? Trends Genet 32:687-688
Presnyak, Vladimir; Alhusaini, Najwa; Chen, Ying-Hsin et al. (2015) Codon optimality is a major determinant of mRNA stability. Cell 160:1111-24
Richter, Joel D; Coller, Jeff (2015) Pausing on Polyribosomes: Make Way for Elongation in Translational Control. Cell 163:292-300
Martin, Sophie; Coller, Jeff (2014) PAN-orama: three convergent views of a eukaryotic deadenylase. Nat Struct Mol Biol 21:577-8
Smith, Jenna E; Alvarez-Dominguez, Juan R; Kline, Nicholas et al. (2014) Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae. Cell Rep 7:1858-66
Geisler, Sarah; Coller, Jeff (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14:699-712
Presnyak, Vlad; Coller, Jeff (2013) The DHH1/RCKp54 family of helicases: an ancient family of proteins that promote translational silencing. Biochim Biophys Acta 1829:817-23
Geisler, Sarah; Lojek, Lisa; Khalil, Ahmad M et al. (2012) Decapping of long noncoding RNAs regulates inducible genes. Mol Cell 45:279-91
Sweet, Thomas; Kovalak, Carrie; Coller, Jeff (2012) The DEAD-box protein Dhh1 promotes decapping by slowing ribosome movement. PLoS Biol 10:e1001342

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