Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's syndrome

Scappaticci, Susi; Cerimele, D; Fraccaro, M.

doi:10.1007/bf00295599

Cited by 82 publications

(49 citation statements)

References 11 publications

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“…Although WS cells show wide genomic instability and hypersensitivity to agents causing DNA damage and in particular interfering with the replication process (Scappaticci et al, 1982;Salk, 1985;Gebhart et al, 1988;Fukuchi et al, 1989;Poot et al, 1999Poot et al, , 2001Pichierri et al, 2000b;Bohr et al, 2001), the precise role for WRN protein in DNA damage response and replication still remains obscure.…”

Section: Discussionmentioning

confidence: 99%

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

2003

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Werner's syndrome (WS) is an autosomal recessive disorder, characterized at the cellular level by genomic instability in the form of variegated translocation mosaicism and extensive deletions. Individuals with WS prematurely develop multiple age-related pathologies and exhibit increased incidence of cancer. WRN, the gene defective in WS, encodes a 160-kDa protein (WRN), which has 3 0 -5 0 exonuclease, DNA helicase and DNAdependent ATPase activities. WRN-defective cells are hypersensitive to certain genotoxic agents that cause replication arrest and/or double-strand breaks at the replication fork, suggesting a pivotal role for WRN in the protection of the integrity of the genoma during the DNA replication process. Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage. However, we provide evidence that WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Finally, we show that WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase.

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Section: Discussionmentioning

confidence: 99%

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

2003

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“…Cells from Werner syndrome cated in yeast aging (reviewed in Jazwinski 2001). Hopatients display genomic translocations and deletions mologs from Caenorhabditis elegans and humans of at (Scappaticci et al 1982;Fukuchi et al 1989). Interestleast three yeast genes (LAG1, SIR2, SGS1) have a similar ingly, Sgs1p as well as Wrn protein is localized in the effect on life span or are able to complement effects nucleolus, suggesting that their role in promoting lonon longevity caused by a mutation in the yeast gene, gevity may be linked to nucleolar function (Sinclair et suggesting that some of the underlying mechanisms may al.…”

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Rtg2 Protein Links Metabolism and Genome Stability in Yeast Longevity

Borghouts¹,

Benguría²,

Wawryn³

et al. 2004

Genetics

137

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Mitochondrial dysfunction induces a signaling pathway, which culminates in changes in the expression of many nuclear genes. This retrograde response, as it is called, extends yeast replicative life span. It also results in a marked increase in the cellular content of extrachromsomal ribosomal DNA circles (ERCs), which can cause the demise of the cell. We have resolved the conundrum of how these two molecular mechanisms of yeast longevity operate in tandem. About 50% of the life-span extension elicited by the retrograde response involves processes other than those that counteract the deleterious effects of ERCs. Deletion of RTG2, a gene that plays a central role in relaying the retrograde response signal to the nucleus, enhances the generation of ERCs in cells with (grande) or in cells without (petite) fully functional mitochondria, and it curtails the life span of each. In contrast, overexpression of RTG2 diminishes ERC formation in both grandes and petites. The excess Rtg2p did not augment the retrograde response, indicating that it was not engaged in retrograde signaling. FOB1, which is known to be required for ERC formation, and RTG2 were found to be in converging pathways for ERC production. RTG2 did not affect silencing of ribosomal DNA in either grandes or petites, which were similar to each other in the extent of silencing at this locus. Silencing of ribosomal DNA increased with replicative age in either the presence or the absence of Rtg2p, distinguishing silencing and ERC accumulation. Our results indicate that the suppression of ERC production by Rtg2p requires that it not be in the process of transducing the retrograde signal from the mitochondrion. Thus, RTG2 lies at the nexus of cellular metabolism and genome stability, coordinating two pathways that have opposite effects on yeast longevity.

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“…Fibroblasts derived from individuals with WS divide many fewer times prior to senescence than do fibroblasts from agematched control individuals (13). Genomic instability has been observed in WS cells, as chromosomal rearrangements (5,19,21) and as mutations within the hypoxanthine phosphoribosyltransferase gene (HPRT); in vivo, an increased frequency of HPRT mutant cells has been observed in patients with WS (2,3,14). The gene defective in WS, WRN, encodes a protein of 1,432 amino acids with similarity to the RecQ subfamily of DNA helicases (26).…”

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confidence: 99%

Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background

Lombard

Beard

Johnson

et al. 2000

Molecular and Cellular Biology

174

129

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Werner's syndrome (WS) is a human disease with manifestations resembling premature aging. The gene defective in WS, WRN, encodes a DNA helicase. Here, we describe the generation of mice bearing a mutation that eliminates expression of the C terminus of the helicase domain of the WRN protein. Mutant mice are born at the expected Mendelian frequency and do not show any overt histological signs of accelerated senescence. These mice are capable of living beyond 2 years of age. Cells from these animals do not show elevated susceptibility to the genotoxins camptothecin or 4-NQO. However, mutant fibroblasts senesce approximately one passage earlier than controls. Importantly, WRN ؊/؊ ; p53 ؊/؊ mice show an increased mortality rate relative to WRN ؉/؊ ; p53 ؊/؊ animals. We consider possible models for the synergy between p53 and WRN mutations for the determination of life span.Werner's Syndrome (WS) is a recessive genetic disease which shows premature onset of many pathologies normally associated with old age (18). Patients with WS appear normal during the first decade of life. The first manifestation of this disease is typically growth failure during adolescence. Subsequently, these patients suffer prematurely from a variety of age-related disorders: skin changes, osteoporosis, diabetes, accelerated atherosclerosis, and cancer, particularly sarcomas. Fibroblasts derived from individuals with WS divide many fewer times prior to senescence than do fibroblasts from agematched control individuals (13). Genomic instability has been observed in WS cells, as chromosomal rearrangements (5,19,21) and as mutations within the hypoxanthine phosphoribosyltransferase gene (HPRT); in vivo, an increased frequency of HPRT mutant cells has been observed in patients with WS (2,3,14). The gene defective in WS, WRN, encodes a protein of 1,432 amino acids with similarity to the RecQ subfamily of DNA helicases (26). Although mutations throughout the WRN gene have been observed in the homozygous state, homozygosity for a mutation very near the 3Ј end of the WRN open reading frame is sufficient to lead to the disease (15).A mouse knockout (KO) of the WRN gene has been described (10). Lebel and Leder deleted exons III and IV in the catalytic helicase domain of the WRN locus, a mutation predicted to eliminate catalytic function. Cells containing this mutation express an internally deleted, nearly full-length WRN protein. Homozygous mutant mice are viable, indicating that this particular mutation is not lethal. However Lebel and Leder showed a decreased embryonic survival of their mutant: on a C57BL/6-129/SvEv outbred background and on a 129/ SvEv inbred background, the ratios of ϩ/ϩ:ϩ/Ϫ:Ϫ/Ϫ mice born are 1:2.0:0.8 and 1:1.9:0.6, respectively. Mutant embryonic stem (ES) cells have an approximately sixfold increased mutation rate at the HPRT locus. They are also 10-fold more sensitive to camptothecin, a topoisomerase I inhibitor, and are two-to threefold more sensitive to etoposide, a topoisomerase II inhibitor. Late-passage mutant embryonic fibro...

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Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's syndrome

Cited by 82 publications

References 11 publications

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

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

Rtg2 Protein Links Metabolism and Genome Stability in Yeast Longevity

Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background

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