Document Detail

Telomerase-independent regulation of ATR by human telomerase RNA.
MedLine Citation:
PMID:  17098743     Owner:  NLM     Status:  MEDLINE    
The human telomerase RNA (hTR), together with the telomerase reverse transcriptase, hTERT, constitute the core components of telomerase that is essential for telomere maintenance. While hTR is ubiquitously expressed, hTERT is normally restricted to germ cells and certain stem cells, but both are often deregulated during tumorigenesis. Here, we investigated the effects of changes in hTR cellular levels. Surprisingly, while inhibition of hTR expression triggers a rapid, telomerase-independent, growth arrest associated with p53 and CHK1 activation, its increased expression neutralizes activation of these pathways in response to genotoxic stress. These hTR effects are mediated through ATR and are sufficiently strong to impair ATR-mediated DNA-damage checkpoint responses. Furthermore, in response to low UV radiation, which activates ATR, endogenous hTR levels increase irrespective of telomerase status. Thus, we uncovered a novel, telomerase-independent, function of hTR that restrains ATR activity and participates in the recovery of cells from UV radiation.
Martijn Kedde; Carlos le Sage; Anja Duursma; Eitan Zlotorynski; Bart van Leeuwen; Wouter Nijkamp; Roderick Beijersbergen; Reuven Agami
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-11-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-12-25     Completed Date:  2007-02-12     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40503-14     Citation Subset:  IM    
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
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MeSH Terms
Cell Cycle / genetics,  radiation effects
Cell Cycle Proteins / antagonists & inhibitors,  metabolism*
Cell Division / genetics,  radiation effects
Cell Line
Cell Line, Tumor
G2 Phase / genetics,  radiation effects
Growth Inhibitors / physiology
Protein Kinases / physiology
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
RNA / physiology*
Signal Transduction / genetics,  radiation effects
Telomerase / antagonists & inhibitors,  biosynthesis,  genetics,  physiology*
Tumor Suppressor Protein p53 / physiology
Ultraviolet Rays
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Growth Inhibitors; 0/Tumor Suppressor Protein p53; 0/telomerase RNA; 63231-63-0/RNA; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC kinase 1; EC Kinases; EC

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