PMID- 20585393
OWN - NLM
STAT- MEDLINE
DCOM- 20110113
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 6
DP  - 2010 Jun 16
TI  - The Werner syndrome protein suppresses telomeric instability caused by chromium 
      (VI) induced DNA replication stress.
PG  - e11152
LID - 10.1371/journal.pone.0011152 [doi]
LID - e11152
AB  - 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 (gammaH2AX) at 
      telomeric foci. The induced gammaH2AX 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 gammaH2AX 
      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.
FAU - Liu, Fu-Jun
AU  - Liu FJ
AD  - Department of Environmental and Occupational Health, University of Pittsburgh 
      Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of 
      America.
FAU - Barchowsky, Aaron
AU  - Barchowsky A
FAU - Opresko, Patricia L
AU  - Opresko PL
LA  - eng
GR  - R01 ES015052/ES/NIEHS NIH HHS/United States
GR  - R01ES015052/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100616
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0R0008Q3JB (Chromium)
RN  - EC 2.7.7.49 (Telomerase)
RN  - EC 3.1.- (Exodeoxyribonucleases)
RN  - EC 3.6.4.12 (RecQ Helicases)
RN  - EC 3.6.4.12 (WRN protein, human)
RN  - EC 3.6.4.12 (Werner Syndrome Helicase)
SB  - IM
MH  - Cell Line
MH  - Chromium/*toxicity
MH  - DNA Replication/*drug effects
MH  - Exodeoxyribonucleases/*physiology
MH  - Humans
MH  - RecQ Helicases/*physiology
MH  - S Phase
MH  - Telomerase/metabolism
MH  - *Telomere
MH  - Werner Syndrome Helicase
PMC - PMC2886837
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/06/30 06:00
MHDA- 2011/01/14 06:00
PMCR- 2010/06/16
CRDT- 2010/06/30 06:00
PHST- 2010/04/07 00:00 [received]
PHST- 2010/05/20 00:00 [accepted]
PHST- 2010/06/30 06:00 [entrez]
PHST- 2010/06/30 06:00 [pubmed]
PHST- 2011/01/14 06:00 [medline]
PHST- 2010/06/16 00:00 [pmc-release]
AID - 10-PONE-RA-17741R1 [pii]
AID - 10.1371/journal.pone.0011152 [doi]
PST - epublish
SO  - PLoS One. 2010 Jun 16;5(6):e11152. doi: 10.1371/journal.pone.0011152.