A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity

Lebel, Michel; Leder, Philip

doi:10.1073/pnas.95.22.13097

Cited by 277 publications

(204 citation statements)

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“…A hypersensitivity of WS cell to CPT has already been reported with the use of several end points (Lebel and Leder, 1998;Poot et al, 1999;Pichierri et al, 2000) and a higher induction of apoptosis has been previously obtained by Poot et al (1999). We confirm the higher induction of apoptosis by CPT in WS cells also after a short pulse treatment.…”

Section: Hypersensitivity Of Ws Cells To Cpt and Husupporting

confidence: 88%

“…The observed sensitivity of WS cells to 4-nitroquinoline-1-oxide (Gebhart et al, 1988;Ogburn et al, 1997) has prompted a search for sensitivity toward drugs that interfere with DNA replication and transcription. More recently, the finding that WS cells show sensitivity to camptothecin, an agent that produces replication-dependent DNA damage, reinforces the hypothesis that WRN functions mainly during the DNA replication processes (Lebel and Leder, 1998;Poot et al, 1999;Pichierri et al, 2000). For these reasons, it has been proposed that the primary defect of this disorder is "unprotected synthesis," that is, the failure of cells to protect the integrity of the genoma during the DNA replication process (Chakraverty and Hickson, 1999).…”

Section: Introductionmentioning

confidence: 82%

“…Noteworthy, yeast mutants in such RecQ-like helicases are extremely sensitive to agents that cause replication arrest, such as hydroxyurea because of uncontrolled illegitimate recombinational events (Stewart et al, 1997;Yamagata et al, 1998). The observed sensitivity of WS cells to 4-nitroquinoline-1-oxide (Gebhart et al, 1988;Ogburn et al (Lebel and Leder, 1998;Poot et al, 1999;Pichierri et al, 2000). For these reasons, it has been proposed that the primary defect of this disorder is "unprotected synthesis," that is, the failure of cells to protect the integrity of the genoma during the DNA replication process (Chakraverty and Hickson, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

Pichierri

Franchitto

Mosesso

et al. 2001

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Werner's syndrome (WS) is a rare autosomal recessive disorder that arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. The cellular function of WRN is still unclear, but on the basis of the cellular phenotypes of WS and of RecQ yeast mutants, its possible role in controlling recombination and/or in maintenance of genomic integrity during S-phase has been envisaged. With the use of two drugs, camptothecin and hydroxyurea, which produce replication-associated DNA damage and/or inhibit replication fork progression, we find that WS cells have a slower rate of repair associated with DNA damage induced in the S-phase and a reduced induction of RAD51 foci. As a consequence, WS cells undergo apoptotic cell death more than normal cells, even if they arrest and resume DNA synthesis at an apparently normal rate. Furthermore, we report that WS cells show a higher background level of DNA strand breaks and an elevated spontaneous induction of RAD51 foci. Our findings support the hypothesis that WRN could be involved in the correct resolution of recombinational intermediates that arise from replication arrest due to either DNA damage or replication fork collapse. INTRODUCTIONWerner's syndrome (WS) is a rare autosomal recessive disorder characterized by premature aging (Salk et al., 1985) and early onset of various neoplasms, including different types of carcinomas and sarcomas (Goto et al., 1981;Hrabko et al., 1982;Sato et al., 1988). This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. One of the hallmarks of WS patients is the genomic instability as evidenced by the spontaneous chromosome anomalies and large deletions in many genes (Salk et al., 1985;Fukuchi et al., 1989). It has been demonstrated that WRN exhibits DNA unwinding activity (Gray et al., 1997;Suzuki et al., 1997) and exonuclease activity residing in the N-terminal region (Huang et al., 1998). The cellular function of WRN is still unclear. It has been proposed that helicases are required for various DNA metabolic activities, including progression of replication fork, segregation of newly replicated chromosomes, disruption of the nucleosome structure, DNA supercoiling, transcription, recombination, and repair (Duguet, 1997). In addition, it has been suggested that RecQ family of DNA helicases has an important role in the maintenance of genomic integrity during DNA replication . Studies from yeast show that DNA replication does not proceed normally in absence of RecQ helicase function (Stewart et al., 1997) and in Xenopus laevis the ortholog of WRN is absolutely required for proper formation of replication foci (Yan et al., 1998). Functional interaction between proteins involved in DNA replication, such as replication protein A (RPA) and DNA polymerase ␦, and WRN also have been reported (Shen et al., 1998;Brosh et al., 1999;Kamath-Loeb et al., 2000). Furthermore, in yeast, the RecQlike proteins seem involved in ...

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Section: Hypersensitivity Of Ws Cells To Cpt and Husupporting

confidence: 88%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

Pichierri

Franchitto

Mosesso

et al. 2001

MBoC

137

140

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“…Mice lacking part of the helicase domain of the Wrn gene were generated by homologous recombination, as described previously (11). In the process, 121 amino acid residues of the Wrn protein were deleted (aa 710 to 831).…”

Section: Animal Modelmentioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

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“…Cataracts, senility and increased incidence of tumors are characteristics of aging not observed in either HGPS patients or the progeric mutant mice for reasons that are not apparent. Attempts at making a mouse model for typical Werner's syndrome have been unsuccessful, despite a 70% sequence homology between the human and mouse genes [25,26]. However the murine Wrn protein is diffusely distributed throughout the nucleus, whereas human WRN protein is primarily restricted to the nucleolus [27] (see Figure 1).…”

Section: Lamins and Diseasementioning

confidence: 99%