Werner Syndrome

Chen, Lishan; Oshima, Junko

doi:10.1155/s1110724302201011

Cited by 50 publications

(49 citation statements)

References 81 publications

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“…Most important, WS patients have a high incidence of malignant neoplasms (1,2). What makes the case even more interesting it is that the tumor type of neoplasms appearing in WS patients is remarkably different from that observed in people who do not have the syndrome: the ratio of mesenchymal:epithelial cancers is 1:1, as compared with 1:10 in the normal aging population (12,32). Thus, it seems that the accelerated aging process in WS patients contributes to the higher incidence of tumors, but the specific loss of the WRN gene confers a particular tumor-type prone phenotype, in a similar fashion to what has been observed with other familial tumor-suppressor genes with DNA-repair function, such as hMLH1 or BRCA1 (33).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

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

241

227

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

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

241

227

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“…39 Individuals with rare genetic diseases that accelerate aging, such as Werner or MDP (Mandibular hypoplasia, Deafness and Progeroid features) syndromes are also known to develop tissue degeneration that affects many organs including the pancreatic gland. Intriguingly, these two syndromes are the result of mutations in genes involved in DNA replication, WRN helicase and DNA polymerase δ catalytic subunit encoding gene POLD1, respectively, 40,41 suggesting that DNA replication stress, such as that exhibited by E2F1/2-deficient cells, may drive tissue involution and aging in some pathological conditions. E2F1 and E2F2 represent controversial players in cell-cycle control, exhibiting dual behavior as tumor suppressors or as oncogenes.…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 99%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

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“…The mutant gene is a member of the RECQ family of helicases together with catalytic and exonuclease activities, and its product probably functions in basic types of DNA transactions, such as replication, repair, recombination, and transcriptional and chromosomal segregation. Recent studies also suggest that RecQ helicases act as genome caretakers (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Frequency of Werner helicase 1367 polymorphism and age-related morbidity in an elderly Brazilian population

Smith

Silva

Araújo

et al. 2005

Braz J Med Biol Res

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Werner syndrome (WS) is a premature aging disease caused by a mutation in the WRN gene. The gene was identified in 1996 and its product acts as a DNA helicase and exonuclease. Some specific WRN polymorphic variants were associated with increased risk for cardiovascular diseases. The identification of genetic polymorphisms as risk factors for complex diseases affecting older people can improve their prevention, diagnosis and prognosis. We investigated WRN codon 1367 polymorphism in 383 residents in a district of the city of São Paulo, who were enrolled in an Elderly Brazilian Longitudinal Study. Their mean age was 79.70 ± 5.32 years, ranging from 67 to 97. This population was composed of 262 females (68.4%) and 121 males (31.6%) of European (89.2%), Japanese (3.3%), Middle Eastern (1.81%), and mixed and/or other origins (5.7%). There are no studies concerning this polymorphism in Brazilian population. These subjects were evaluated clinically every two years. The major health problems and morbidities affecting this cohort were cardiovascular diseases (21.7%), hypertension (83.7%), diabetes (63.3%), obesity (41.23%), dementia (8.0%), depression (20.0%), and neoplasia (10.8%). Their prevalence is similar to some urban elderly Brazilian samples. DNA was isolated from blood cells, amplified by PCR and digested with PmaCI. Allele frequencies were 0.788 for the cysteine and 0.211 for the arginine. Genotype distributions were within that expected for the Hardy-Weinberg equilibrium. Female gender was associated with hypertension and obesity. Logistic regression analysis did not detect significant association between the polymorphism and morbidity. These findings confirm those from Europeans and differ from Japanese population.

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Werner Syndrome

Cited by 50 publications

References 81 publications

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

Frequency of Werner helicase 1367 polymorphism and age-related morbidity in an elderly Brazilian population

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