Spontaneous and induced chromosomal instability in Werner syndrome

Gebhart, Erich; Bauer, Ralph H.; Raub, U.; Schinzel, Margot; Ruprecht, Klaus W.; Jonas, Jost B.

doi:10.1007/bf00702855

Cited by 141 publications

(104 citation statements)

References 20 publications

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“…3 A and B and Table 1). This result is in accordance with previously published studies, mostly carried out in WS patient lymphocytes, where large deletions, breaks, and reciprocal translocations were reported (6,7,26). The appearance of these chromosomal aberrations is also consistent with the formation of chromosome fusions quickly after suppression of DNA damage checkpoints in WS cells.…”

Section: Resultssupporting

confidence: 93%

Telomere dysfunction as a cause of genomic instability in Werner syndrome

Crabbé

Jauch

Naeger

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

213

167

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Werner syndrome (WS) is a rare human premature aging disease caused by mutations in the gene encoding the RecQ helicase WRN. In addition to the aging features, this disorder is marked by genomic instability, associated with an elevated incidence of cancer. Several lines of evidence suggest that telomere dysfunction is associated with the aging phenotype of the syndrome; however, the origin of the genomic instability observed in WS cells and the reason for the high incidence of cancer in WS have not been established. We previously proposed that WRN helicase activity was necessary to prevent dramatic telomere loss during DNA replication. Here we demonstrate that replication-associated telomere loss is responsible for the chromosome fusions found in WS fibroblasts. Moreover, using metaphase analysis we show that telomere elongation by telomerase can significantly reduce the appearance of new chromosomal aberrations in cells lacking WRN, similar to complementation of WS cells with WRN. Our results suggest that the genome instability in WS cells depends directly on telomere dysfunction, linking chromosome end maintenance to chromosomal aberrations in this disease.cancer ͉ WRN ͉ genome instability ͉ aging

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Section: Resultssupporting

confidence: 93%

Telomere dysfunction as a cause of genomic instability in Werner syndrome

Crabbé

Jauch

Naeger

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

213

167

View full text Add to dashboard Cite

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“…This observation is consistent with the possibility that in the absence of active WRN the spontaneous damage at the replication fork cannot be resolved properly, leading to recruitment of HR molecular apparatus. In addition, persistence of DNA strand breaks in WS cells could be consistent with the observed higher rate of DNA rearrangements (Gebhart et al, 1988;Fukuchi et al, 1989). Furthermore, a possible consequence of this higher yield of DNA strand breaks is that the effect of the reported interruption of RNA synthesis by CPT, which results in an SSB in the transcribed strand (Barrows et al, 1998;Mosesso et al, 2000), combined with one gap in the other strand, could lead to cytotoxic DSB in G2 cells, thus resulting in cell death.…”

Section: Lack Of Functional Wrn Protein Results In Higher Spontaneoussupporting

confidence: 72%

“…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, 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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

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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

138

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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“…The mechanism underlying the 4NQO sensitivity of WS cell lines is not known. 4NQO produces bulky DNA adducts, oxidative damage, and strand breaks (Gebhart et al, 1988), and the lesions are generally thought to be repaired by NER (Jones et al, 1989). 4NQO has often been referred to as a UV mimetic, and 66 genes overlapped between the 4NQO and UV response vs 15 between 4NQO and g-irradiation (see Supplementary Table 4).…”

Section: Discussionmentioning

confidence: 99%

Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

et al. 2005

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The accumulation of DNA damage and mutations is considered a major cause of cancer and aging. While it is known that DNA damage can affect changes in gene expression, transcriptional regulation after DNA damage is poorly understood. We characterized the expression of 6912 genes in human primary fibroblasts after exposure to three different kinds of cellular stress that introduces DNA damage: 4-nitroquinoline-1-oxide (4NQO), c-irradiation, or UV-irradiation. Each type of stress elicited damage specific gene expression changes of up to 10-fold. A total of 85 genes had similar changes in expression of 3-40-fold after all three kinds of stress. We examined transcription in cells from young and old individuals and from patients with Werner syndrome (WS), a segmental progeroid condition with a high incidence of cancer, and found various age-associated transcriptional changes depending upon the type of cellular stress. Compared to young individuals, both WS and old individuals had similarly aberrant transcriptional responses to c-and UV-irradiation, suggesting a role for Werner protein in stress-induced gene expression. Our results suggest that aberrant DNA damage-induced gene regulation may contribute to the aging process and the premature aging in WS.

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Spontaneous and induced chromosomal instability in Werner syndrome

Cited by 141 publications

References 20 publications

Telomere dysfunction as a cause of genomic instability in Werner syndrome

Telomere dysfunction as a cause of genomic instability in Werner syndrome

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

Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

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