Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease

@article{Bird2011RecapitulationOW,
  title={Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease},
  author={Joe L.E. Bird and Katrin Jennert-Burston and Marcus A. Bachler and Penelope A. Mason and Jillian E. Lowe and S J Heo and Judith Campisi and R G A Faragher and Lynne S. Cox},
  journal={Biogerontology},
  year={2011},
  volume={13},
  pages={49-62}
}
WRN is a RecQ helicase with an associated exonuclease activity important in DNA metabolism, including DNA replication, repair and recombination. In humans, deficiencies in WRN function cause the segmental progeroid Werner syndrome (WS), in which patients show premature onset of many hallmarks of normal human ageing. At the cellular level, WRN loss results in rapid replicative senescence, chromosomal instability and sensitivity to various DNA damaging agents including the topoisomerase inhibitor… Expand
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References

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Camptothecin Sensitivity in Werner Syndrome Fibroblasts as Assessed by the COMET Technique
TLDR
The COMET (single‐cell gel electrophoresis) assay is a rapid, sensitive, versatile, and robust technique for the quantitative assessment of DNA damage in eukaryotic cells and is found that a significantly increased level of strand breaks can be demonstrated in WS cells treated with camptothecin compared with normal controls. Expand
Correction of proliferation and drug sensitivity defects in the progeroid Werner's Syndrome by Holliday junction resolution.
TLDR
This work is the first to demonstrate that Holliday junction accumulation in primary Werner syndrome fibroblasts results in their poor proliferative capacity, and to rescue WS hypersensitivity to camptothecin and 4NQO by Holliday Junction resolution. Expand
Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase
TLDR
It is hypothesized that, in cells deficient for WRN function, a topoisomerase-I-DNA intermediate persists, and conflict with DNA replication may lead to apoptosis, increased mutation rates, and cancer in WRN. Expand
Replication fork regression in vitro by the Werner syndrome protein (WRN): Holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity
TLDR
A role for WRN in regression of blocked replication forks is strongly supported, along with the established cellular consequences of WRN deficiency, to suggest that the multiple activities ofWRN cooperate to promote replication fork regression. Expand
A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity.
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  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1998
TLDR
It is shown that the gene responsible for Werner syndrome encodes a member of the RecQ-like subfamily of DNA helicases and its murine homologue maps to murine chromosome 8 in a region syntenic with the human WRN gene. Expand
Werner syndrome protein: Functions in the response to DNA damage and replication stress in S-phase
TLDR
Future research should focus on the mechanism(s) of WRN in the regulation of the various DNA metabolism pathways and development of therapeutic approaches to treat premature aging syndromes such as WS. Expand
Werner Syndrome Protein and the MRE11 Complex are Involved in a Common Pathway of Replication Fork Recovery
TLDR
A functional relationship between WRN and the MRE11 complex in response to replication fork arrest is suggested, disclosing a common action of WRN in the pathway(s) preserving genome stability during DNA replication. Expand
The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest
TLDR
Cell cycle kinetics during normal cell division and after methyl-methane-sulfonate DNA damage or hydroxyurea-mediated replication arrest show that WRN depletion significantly reduced the speed at which replication forks elongated in vivo after MMS or HU treatment, establishing the importance of WRN during genomic replication and indicating thatWRN acts to facilitate fork progression afterDNA damage or replication arrest. Expand
Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase.
TLDR
A potential combination therapy of WRN-siRNA and CPT is proposed, looking forward to minimizing the inevitable adverse effects associated with cancer chemotherapy. Expand
Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells
TLDR
This paper reviews the events that show a close correlation of the WRN gene and WRN with carcinogenesis and their underlying molecular mechanisms and discusses the sensitivity of cells against various genotoxins, including camptothecin. Expand
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