Document Detail

CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila.
MedLine Citation:
PMID:  23154984     Owner:  NLM     Status:  MEDLINE    
A conserved transcriptional feedback loop underlies animal circadian rhythms. In Drosophila, the transcription factors CLOCK (CLK) and CYCLE (CYC) activate the transcription of direct target genes like period (per) and timeless (tim). They encode the proteins PER and TIM, respectively, which repress CLK/CYC activity. Previous work indicates that repression is due to a direct PER-CLK/CYC interaction as well as CLK/CYC phosphorylation. We describe here the role of ubiquitin-specific protease 8 (USP8) in circadian transcriptional repression as well as the importance of CLK ubiquitylation in CLK/CYC transcription activity. usp8 loss of function (RNAi) or expression of a dominant-negative form of the protein (USP8-DN) enhances CLK/CYC transcriptional activity and alters fly locomotor activity rhythms. Clock protein and mRNA molecular oscillations are virtually absent within circadian neurons of USP8-DN flies. Furthermore, CLK ubiquitylation cycles robustly in wild-type flies and peaks coincident with maximal CLK/CYC transcription. As USP8 interacts with CLK and expression of USP8-DN increases CLK ubiquitylation, the data indicate that USP8 deubiquitylates CLK, which down-regulates CLK/CYC transcriptional activity. Taken together with the facts that usp8 mRNA cycles and that its transcription is activated directly by CLK/CYC, USP8, like PER and TIM, contributes to the transcriptional feedback loop cycle that underlies circadian rhythms.
Weifei Luo; Yue Li; Chih-Hang Anthony Tang; Katharine C Abruzzi; Joseph Rodriguez; Stefan Pescatore; Michael Rosbash
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes & development     Volume:  26     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-16     Completed Date:  2013-01-17     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2536-49     Citation Subset:  IM    
Howard Hughes Medical Institute.
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MeSH Terms
ARNTL Transcription Factors / genetics*,  metabolism
CLOCK Proteins / genetics*,  metabolism*
Circadian Rhythm / genetics
Drosophila Proteins / genetics*,  metabolism*
Drosophila melanogaster / enzymology,  genetics,  metabolism,  physiology*
Gene Expression Regulation
Motor Activity / genetics
Period Circadian Proteins / metabolism
Protein Isoforms
RNA Interference
Ubiquitin Thiolesterase / metabolism*
Grant Support
P01 NS44232/NS/NINDS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/ARNTL Transcription Factors; 0/CYCLE protein, Drosophila; 0/Clk protein, Drosophila; 0/Drosophila Proteins; 0/PER protein, Drosophila; 0/Period Circadian Proteins; 0/Protein Isoforms; 0/timeless protein, Drosophila; EC Proteins; EC Thiolesterase

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