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The Werner syndrome protein suppresses telomeric instability caused by chromium (VI) induced DNA replication stress

Liu, FJ and Barchowsky, A and Opresko, PL (2010) The Werner syndrome protein suppresses telomeric instability caused by chromium (VI) induced DNA replication stress. PLoS ONE, 5 (6).

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Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)- induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)- induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration. © 2010 Liu et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Liu, FJ
Barchowsky, Aaab20@pitt.eduAAB20
Opresko, PLplo4@pitt.eduPLO4
ContributionContributors NameEmailPitt UsernameORCID
Date: 11 August 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0011152
Schools and Programs: School of Public Health > Environmental and Occupational Health
Refereed: Yes
MeSH Headings: Cell Line; Chromium--toxicity; DNA Replication--drug effects; Exodeoxyribonucleases--physiology; Humans; RecQ Helicases--physiology; S Phase; Telomerase--metabolism; Telomere
Other ID: NLM PMC2886837
PubMed Central ID: PMC2886837
PubMed ID: 20585393
Date Deposited: 03 Aug 2012 21:01
Last Modified: 02 Feb 2019 15:55


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