Document Detail


Flap endonuclease 1 contributes to telomere stability.
MedLine Citation:
PMID:  18394896     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Telomere stability plays an important role in the preservation of genomic stability and is maintained through the coordinated actions of telomere-specific proteins and DNA repair and replication proteins [1, 2]. Flap endonuclease 1 (FEN1) is a protein that plays a role in lagging-strand DNA replication, base excision repair, homologous recombination, and reinitiation of stalled replication forks [3, 4]. Here, we demonstrate that FEN1 depletion leads to telomere dysfunction characterized by the presence of gammaH2AX and sister telomere loss. Expression of catalytically active telomerase, the reverse transcriptase that adds telomeric repeats to chromosome ends, was sufficient to rescue telomere dysfunction upon FEN1 depletion. Strikingly, FEN1 depletion exclusively abrogates telomeres replicated by lagging-strand DNA replication. Genetic rescue experiments utilizing FEN1 mutant proteins that retained the ability to localize to telomeric repeats revealed that FEN1's nuclease activity and ability to interact with the Werner protein (WRN) and telomere-binding protein (TRF2) were required for FEN1 activity at the telomere. Given FEN1's role in lagging-strand DNA replication and reinitiation of stalled replication forks, we propose that FEN1 contributes to telomere stability by ensuring efficient telomere replication.
Authors:
Abhishek Saharia; Lionel Guittat; Sandra Crocker; Adeline Lim; Martin Steffen; Shashikant Kulkarni; Sheila A Stewart
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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:  Current biology : CB     Volume:  18     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-09     Completed Date:  2008-07-31     Revised Date:  2013-04-03    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  496-500     Citation Subset:  IM    
Affiliation:
Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
DNA Replication / physiology*
Flap Endonucleases / metabolism*
Humans
Telomere / metabolism*
Grant Support
ID/Acronym/Agency:
F32 CA093033/CA/NCI NIH HHS; P41-RR00954/RR/NCRR NIH HHS; R21 AG025320-01/AG/NIA NIH HHS; R21 AG025320-02/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
EC 3.1.-/Flap Endonucleases; EC 3.1.11.-/FEN1 protein, human
Comments/Corrections

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