Werner’s Syndrome Associated with Malignancies:Five Case Reports with a Survey of Case Histories in Japan

Sato, Kanji; Goto, Makoto; Nishioka, Keiko; Arima, Kota; Hori, Natsuki; Yamashita, Nobuaki; Fujimoto, Yohei; Nanko, Hiroko; Ohara, Kazunori

doi:10.1159/000212956

Cited by 32 publications

(13 citation statements)

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“…Werner'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.…”

Section: Introductionmentioning

confidence: 99%

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

136

140

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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: Introductionmentioning

confidence: 99%

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

136

140

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“…Werner syndrome (WS) 1 is a rare disorder characterized by the premature onset of a number of processes associated with aging (1,2). In addition, the proliferative life span of WS fibroblasts is reduced compared with age-matched controls (3)(4)(5).…”

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confidence: 99%

The Werner Syndrome Gene Product Co-purifies with the DNA Replication Complex and Interacts with PCNA and Topoisomerase I

Lebel¹,

Spillare²,

Harris³

et al. 1999

Journal of Biological Chemistry

233

168

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Werner syndrome (WS) is a recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases. To understand the molecular basis of this disease, we deleted a segment of the murine Wrn gene and created Wrn-deficient embryonic stem (ES) cells. At the molecular level, wild type-but not mutant-WS protein co-purifies through a series of centrifugation, chromatography, and sucrose gradient steps with the well characterized 17 S multiprotein DNA replication complex. Furthermore, wild type WS protein co-immunoprecipitates with a prominent component of the multiprotein replication complex, proliferating cell nuclear antigen (PCNA). In vitro studies also indicate that PCNA binds to a region in the N terminus portion of the WS protein containing a potential 3-5 exonuclease domain. Finally, human WS protein also co-immunoprecipitates with both PCNA and topoisomerase I. These results suggest that the WS protein interacts with several components of the DNA replication fork.Werner syndrome (WS) 1 is a rare disorder characterized by the premature onset of a number of processes associated with aging (1, 2). In addition, the proliferative life span of WS fibroblasts is reduced compared with age-matched controls (3)(4)(5). WS cells from patients also exhibit genomic abnormalities such as variegated chromosomal translocations and deletions (6, 7). Most recently, WS cells have been shown to have an attenuation of a p53-dependent apoptotic pathway (8).The WS gene (WRN) product contains seven helicase consensus domains that are 34 -38% identical to the Escherichia coli RecQ gene (9,10) and to the putative yeast helicase Sgs1p (11,12). The Sgs1p is known to interact with types I and II topoisomerases and is required for genome stability in Saccharomyces cerevisiae (11)(12)(13). In addition, an interesting model involving the promotion of extrachromosomal rDNA circles has been proposed for the aging phenotype in yeast Sgs1 mutants (14). Several studies suggest that the WS protein may be implicated in some aspect of DNA replication. WS cells show a prolongation of the S phase of the cell cycle and a decreased rate of DNA synthesis (15). Interestingly, the homologue of the human Werner syndrome gene product in Xenopus laevis is required for the formation of replication foci in egg extracts (16).To study the possible interaction of the mouse WS protein with the DNA replication apparatus, we recently created a deletion of part of the helicase domain of the murine homologue of the WS gene in embryonic stem (ES) cells (17). Biochemical studies of our ES cell lines allowed us to conclude that the WS protein co-purifies with the DNA replication complex and binds to certain of its specific components. EXPERIMENTAL PROCEDURESProtein Analysis-Generation and maintenance of the wild type and homozygous mutant embryonic stem cells have been described previously (17). Protein extraction, immunoprecipitations, and Western blotting analyses were performed as described (8,18). A rabbit polyclonal anti...

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“…These findings suggest that WSis a chromosome instability syndromeand that patients with this syndromemay have genetic mutations which are associated with premature senescence and higher tumor frequency compared with normal persons. According to the analysis of approximately 300 cases of WSreported in Japan, the incidence of malignancy in WSis thought to be about 14% (5). Malignancies in the thyroid gland are reported to be relatively common (2).…”

Section: Case Reportmentioning

confidence: 99%

“…Although rare, nine cases which showedthe onset of leukemia while undergoing treatment for WShave been previously reported. In these reports normal woman's karyotype (46, XX) (3) and abnormal karyotype (44, XY, -3, -B, C, -F, +mar, +mar, +mar) (4) were discussed, but no investigation ofchromosomal changes or genetic mutations was done for the progression of myelodysplastic syndrome (MDS) in WS (5). We treated a rare case ofMDSthat advanced to overt leukemia in the background of chromosomal instability syndrome as WS, and its progression was thought to be related to the genetic change.…”

Section: Introductionmentioning

confidence: 96%

Leukemia Developing after 131I Treatment for Thyroid Cancer in a Patient with Werner's Syndrome: Molecular and Cytogenetic Studies.

et al. 1995

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Werner’s Syndrome Associated with Malignancies:Five Case Reports with a Survey of Case Histories in Japan

Cited by 32 publications

References 10 publications

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

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

The Werner Syndrome Gene Product Co-purifies with the DNA Replication Complex and Interacts with PCNA and Topoisomerase I

Leukemia Developing after 131I Treatment for Thyroid Cancer in a Patient with Werner's Syndrome: Molecular and Cytogenetic Studies.

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