? Faithful maintenance of translational reading frame is a basic requirement for translation of genetic information from genes into proteins. Exceptions to this rule have been characterized mostly in RNA viruses, where specific cis-acting mRNA signals induce elongating ribosomes to shift reading frame. Given that many basic biological regulatory mechanisms have been first in viral systems, we hypothesize that programmed ribosomal frameshifting is utilized to regulate the expression of a significant subset of cellular genes as well. If so, this would represent a significant shift in our view of protein translation, and may have significant impact on our understanding of many of the underlying causes of birth defects, cancer and aging. Preliminary studies are presented supporting this hypothesis. These include bioinformatic, RNA-blot, and a preliminary set of DNA microarray analyses. The proposed studies will expand upon a DNA microarray approach to identify cellular mRNAs that are regulated by programmed -1 ribosomal frameshifting (-1 PRF). The overall strategy will be to identify cellular mRNAs that are specifically stabilized under conditions where -1 PRF is inhibited, and conversely, those that are destabilized when -1 PRF is stimulated. The data generated from these experiments will be compared with one another and with our database of consensus -1 PRF signal containing genes in order to identify the best candidates for further characterization with regard to the role that -1 PRF may play in theregulation of their expression. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21GM068123-01
Application #
6612443
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Rhoades, Marcus M
Project Start
2003-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$111,375
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Belew, Ashton Trey; Meskauskas, Arturas; Musalgaonkar, Sharmishtha et al. (2014) Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. Nature 512:265-9
Advani, Vivek M; Belew, Ashton T; Dinman, Jonathan D (2013) Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway. Translation (Austin) 1:e24418
Dinman, Jonathan D (2012) Mechanisms and implications of programmed translational frameshifting. Wiley Interdiscip Rev RNA 3:661-73
Belew, Ashton T; Advani, Vivek M; Dinman, Jonathan D (2011) Endogenous ribosomal frameshift signals operate as mRNA destabilizing elements through at least two molecular pathways in yeast. Nucleic Acids Res 39:2799-808
Belew, Ashton T; Hepler, Nicholas L; Jacobs, Jonathan L et al. (2008) PRFdb: a database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals. BMC Genomics 9:339
Jacobs, Jonathan L; Belew, Ashton T; Rakauskaite, Rasa et al. (2007) Identification of functional, endogenous programmed -1 ribosomal frameshift signals in the genome of Saccharomyces cerevisiae. Nucleic Acids Res 35:165-74
Dinman, Jonathan D (2006) Programmed Ribosomal Frameshifting Goes Beyond Viruses: Organisms from all three kingdoms use frameshifting to regulate gene expression, perhaps signaling a paradigm shift. Microbe Wash DC 1:521-527
Plant, Ewan P; Wang, Pinger; Jacobs, Jonathan L et al. (2004) A programmed -1 ribosomal frameshift signal can function as a cis-acting mRNA destabilizing element. Nucleic Acids Res 32:784-90
Jacobs, Jonathan L; Dinman, Jonathan D (2004) Systematic analysis of bicistronic reporter assay data. Nucleic Acids Res 32:e160