Document Detail

Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay.
MedLine Citation:
PMID:  23766421     Owner:  NLM     Status:  MEDLINE    
UPF1 is a DNA/RNA helicase with essential roles in nonsense-mediated mRNA decay (NMD) and embryonic development. How UPF1 regulates target abundance and the relationship between NMD and embryogenesis are not well understood. To explore how NMD shapes the embryonic transcriptome, we integrated genome-wide analyses of UPF1 binding locations, NMD-regulated gene expression, and translation in murine embryonic stem cells (mESCs). We identified over 200 direct UPF1 binding targets using crosslinking/immunoprecipitation-sequencing (CLIP-seq) and revealed a repression pathway that involves 3' UTR binding by UPF1 and translation but is independent of canonical targeting features involving 3' UTR length and stop codon placement. Interestingly, NMD targeting of this set of mRNAs occurs in other mouse tissues and is conserved in human. We also show, using ribosome footprint profiling, that actively translated upstream open reading frames (uORFs) are enriched in transcription factor mRNAs and predict mRNA repression by NMD, while poorly translated mRNAs escape repression. Together, our results identify novel NMD determinants and targets and provide context for understanding the impact of UPF1 and NMD on the mESC transcriptome.
Jessica A Hurt; Alex D Robertson; Christopher B Burge
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-06-13
Journal Detail:
Title:  Genome research     Volume:  23     ISSN:  1549-5469     ISO Abbreviation:  Genome Res.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-02     Completed Date:  2014-04-07     Revised Date:  2014-04-15    
Medline Journal Info:
Nlm Unique ID:  9518021     Medline TA:  Genome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1636-50     Citation Subset:  IM    
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MeSH Terms
3' Untranslated Regions*
Binding Sites / genetics
Codon, Terminator
Embryonic Stem Cells / metabolism*
Evolution, Molecular
Gene Expression Regulation*
Mice, Inbred C57BL
Nonsense Mediated mRNA Decay*
Open Reading Frames
Protein Biosynthesis
RNA, Messenger / metabolism*
Sequence Analysis, RNA
Trans-Activators / genetics,  metabolism*
Transcription Factors / metabolism
Grant Support
Reg. No./Substance:
0/3' Untranslated Regions; 0/Codon, Terminator; 0/RNA, Messenger; 0/Rent1 protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 0/UPF1 protein, human

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