Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells

@article{Futami2008RoleOW,
  title={Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells},
  author={Kazunobu Futami and Yuichi Ishikawa and Makoto Goto and Yasuhiro Furuichi and Masanobu Sugimoto},
  journal={Cancer Science},
  year={2008},
  volume={99}
}
Werner syndrome (WS) is an autosomal recessive genetic disorder causing premature aging, and WRN has been identified as the causative gene of WS. The product of the WRN gene (WRN) acts as a DNA helicase with exonuclease activity, and data have accumulated showing that the WRN gene strongly participates in carcinogenesis: (1) the normal WRN gene likely participates in the immortalization of B‐lymphoblastoid cell lines through telomeric crisis caused by telomere shortening, (2) a much higher… Expand
WRN, the Werner Syndrome Gene, Exhibits Frameshift Mutations in Gastric and Colorectal Cancers
TLDR
Cancer-related functions (DNA repair and maintenance of genomic stability) and increased cancer incidence in Werner syndrome led to the analysis of inactivating mutations of WRN gene in GC and CRC, which found aberrant bands represented WRN somatic mutations. Expand
Involvement of WRN helicase in immortalization and tumorigenesis by the telomeric crisis pathway (Review).
TLDR
The proposed WRN helicase encoded by the WRN gene is required for immortalization by the telomeric crisis pathway (TCP) in a system that uses lymphoblastoid cell lines transformed by the Epstein-Barr virus, and the ratio of epithelial to non-epithelial cancers is approximately 1:1 in WS patients compared to 10: 1 in the general population. Expand
WRN translocation from nucleolus to nucleoplasm is regulated by SIRT1 and required for DNA repair and the development of chemoresistance.
TLDR
The results suggest that WRN is regulated by SIRT1 and increased expression of WRN might be one of the determinants for the development of chemotherapeutic drug resistance. Expand
Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease
TLDR
It is shown that targeting WRN mRNA for degradation by either RNAi or hammerhead ribozyme catalysis renders human fibroblasts as sensitive to CPT as fibro Blasts derived from WS patients, and furthermore, altered cell cycle transit and nucleolar destabilisation in these cells following CPT treatment are found. Expand
Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells
TLDR
It is demonstrated that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress, and supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN‐knockdown cancer cells. Expand
A cascade leading to premature aging phenotypes including abnormal tumor profiles in Werner syndrome (review).
  • M. Sugimoto
  • Medicine, Biology
  • International journal of molecular medicine
  • 2014
TLDR
A hypothetical mechanism of premature aging in WS is described: telomere dysfunction induced by WRN mutation causes multiple premature aging phenotypes of WS, including shortened cellular lifespan and inflammation induced by ROS, such as diabetes mellitus. Expand
Roles of Werner syndrome protein in protection of genome integrity.
TLDR
Some of the early studies on the cellular roles of Werner syndrome protein are summarized and the recent findings that shed some light on the link between the protein with its cellular functions and the disease pathology are highlighted. Expand
Functional deficit associated with a missense Werner syndrome mutation.
TLDR
Biochemical experiments with purified mutant recombinant WRN protein showed that the G574R mutation inhibits ATP binding, and thereby leads to significant decrease in helicase activity, which could be responsible for the Werner syndrome phenotype in the patient. Expand
The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis
TLDR
The clinical, molecular and biochemical characteristics of WS are described for use by medical professionals in a health care setting and are of potential interest to measure WRN activities in WS patients. Expand
RECQL1 and WRN DNA repair helicases: potential therapeutic targets and proliferative markers against cancers
TLDR
These findings indicate that RECQL1 and WRN helicases are ideal molecular targets for cancer therapy and introduce efforts to develop anticancer RecQ-siRNA drugs free from adverse effects. Expand
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References

SHOWING 1-10 OF 50 REFERENCES
Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer.
  • R. Agrelo, W. Cheng, +12 authors M. Esteller
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
It is reported that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation, and the importance of WRN epigenetic inactivation inhuman cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs is highlighted. Expand
A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity.
  • M. Lebel, P. Leder
  • 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 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
Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle
TLDR
It is shown that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage, but there is no evidence thatWRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Expand
Molecular biology of Werner syndrome
TLDR
Human RecQ helicases, including the Werner syndrome helicase, participate in maintaining the integrity of the genome by suppressing illegitimate recombination or by repair of local DNA structural damage, and genomic instability increases the risk of the development of neoplasms, both benign and malignant. Expand
Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing*
  • Baomin Li, L. Comai
  • Biology, Medicine
  • The Journal of Biological Chemistry
  • 2000
TLDR
Protein-protein interaction studies reveal that WRN binds directly to Ku80 and that this interaction is mediated by the amino terminus of WRN and shows that the binding of Ku alters the specificity of the WRN exonuclease, suggesting a potential involvement ofWRN in the repair of double strand DNA breaks. Expand
The Werner Syndrome Gene Product Co-purifies with the DNA Replication Complex and Interacts with PCNA and Topoisomerase I*
TLDR
Results suggest that the WS protein interacts with several components of the DNA replication fork, including topoisomerase I and PCNA. Expand
Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes.
TLDR
The results show that AF and WS cells are hypersensitive to VP16, as revealed in the higher proportion of metaphases showing exchange figures and more than two breaks, which underline the fact that VP16 damage is amplified only in cells that have abnormal illegitimate recombination. Expand
Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity
TLDR
A novel interaction of the WRN gene product with the human 5′ flap endonuclease/5′–3′ exonuclelease (FEN‐1), a DNA structure‐specific nuclease implicated in DNA replication, recombination and repair is reported. Expand
DNA Damage-induced Translocation of the Werner Helicase Is Regulated by Acetylation*
TLDR
It is shown that UV exposure leads to extensive translocation of WRN from the nucleolus to nucleoplasmic foci in a dose-dependent manner, and this support the notion that WRN plays a role in the cellular response to DNA damage and suggest that the activity ofWRN is modulated by DNA damage-induced post-translational modifications of WRn and possibly WRN-interacting proteins. Expand
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