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).
Abstract
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
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| Status: |
Published |
| Creators/Authors: |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID  |
|---|
| Editor | Blagosklonny, Mikhail V. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13378 |
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