Telomere dysfunction as a cause of genomic instability in Werner syndrome

Crabbé, Laure; Jauch, Anna; Naeger, Colleen M.; Holtgreve-Grez, Heidi; Karlseder, Jan

doi:10.1073/pnas.0609410104

Cited by 213 publications

(174 citation statements)

References 33 publications

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“…Covalent fusion of the chromosomal ends may induce genomic instability due to the random DNA break during anaphase [50]. It has recently been proposed that replication-associated telomere loss and resultant chromosome fusions may be the cause of genomic instability seen in the classical Werner syndrome caused by WRN helicase gene mutations [51]. It is conceivable that the increased apoptosis [19] and DNA accumulation [52] seen in HGPS may be, at least in part, secondary to accelerated telomere loss.…”

Section: Discussionmentioning

confidence: 99%

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Huang

Risques

Martin

et al. 2008

Experimental Cell Research

116

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LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectible WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes.

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Section: Discussionmentioning

confidence: 99%

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Huang

Risques

Martin

et al. 2008

Experimental Cell Research

116

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“…Subsequently, the mouse Mgs1 orthologue, Wrnip1 (Werner-interacting protein 1) was cloned as a binder of the helicase (Wrn) mutated in the Werner syndrome (4,5). Telomere aberrations and defective telomere laggingstrand replication have been proposed to be a key patho-mechanism of this very rare premature aging condition, which remarkably recapitulates the main features of physiological aging (6,7). In S. cerevisiae, mgs1 was found to be synthetically lethal with the rad6 and rad18 genes involved in DNA damage tolerance, indicating that Mgs1/Wrnip1 might deal with stalled replication forks (8).…”

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confidence: 99%

Human Wrnip1 Is Localized in Replication Factories in a Ubiquitin-binding Zinc Finger-dependent Manner

Crosetto

Bienko

Hibbert

et al. 2008

Journal of Biological Chemistry

102

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Wrnip1 (Werner helicase-interacting protein 1) has been implicated in the bypass of stalled replication forks in bakers' yeast. However, the function(s) of human Wrnip1 has remained elusive so far. Here we report that Wrnip1 is distributed inside heterogeneous structures detectable in nondamaged cells throughout the cell cycle. In an attempt to characterize these structures, we found that Wrnip1 resides in DNA replication factories. Upon treatments that stall replication forks, such as UVC light, the amount of chromatin-bound Wrnip1 and the number of foci significantly increase, further implicating Wrnip1 in DNA replication. Interestingly, the nuclear pattern of Wrnip1 appears to extend to a broader landscape, as it can be detected in promyelocytic leukemia nuclear bodies. The presence of Wrnip1 into these heterogeneous subnuclear structures requires its ubiquitin-binding zinc finger (UBZ) domain, which is able to interact with different ubiquitin (Ub) signals, including mono-Ub and chains linked via lysine 48 and 63. Moreover, the oligomerization of Wrnip1 mediated by its C terminus is also important for proper subnuclear localization. Our study is the first to reveal the composite and regulated topography of Wrnip1 in the human nucleus, highlighting its potential role in replication and other nuclear transactions.

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“…Although prior experiments have shown that suppression of the pRb and p53 DNA damage checkpoint pathways by viral oncoproteins enables bypass of replicative senescence in WS cells (16)(17)(18), to our knowledge there have not been any experimental investigations of the neoplastic conversion of WS cells or the properties of cancer cells from WS patients. In previous studies we showed that normal human fibroblasts require only the combination of oncogenic Ras and SV40 large T antigen (SV40 LT) to be converted to fully tumorigenic cells, as evidenced by their ability to form invasive and metastatic tumors in the subrenal capsule assay in immunodeficient mice (19,20).…”

Section: Introductionmentioning

confidence: 96%

Fibroblasts from Werner syndrome patients: Cancer cells derived by experimental introduction of oncogenes maintain malignant properties despite entering crisis

Hornsby¹

2009

Oncol Rep

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Abstract. Werner syndrome (WS) results from defects in the gene encoding WRN RecQ helicase. WS fibroblasts undergo premature senescence in culture. Because cellular senescence is a tumor suppressor mechanism, we examined whether WS fibroblasts exhibited reduced tumorigenicity, in comparison to control cells, in a model of experimental conversion of normal human cells to cancer cells. The combination of oncogenic Ras (Ha-Ras V12G ) and SV40 large T antigen (SV40 LT) causes human cells to acquire neoplastic properties in the absence of telomerase. We found that WS cells could also be converted to a tumorigenic state by these oncogenes, as evidenced by invasion and metastasis of cells implanted in immunodeficient mice. Ras/SV40 LT-expressing cells retained invasiveness and malignant properties even when cells reached crisis in tumors in vivo. High levels of gelatinase were found by an in situ assay in Ras/SV40 LT-expressing cells undergoing crisis. We conclude that, despite evidence of accelerated senescence in WS cells, there is no evidence that the absence of active WRN acts as a barrier to neoplastic transformation. Moreover, we find that tumorigenic human cells retain malignant properties of the cells as they approach and reach crisis.

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Telomere dysfunction as a cause of genomic instability in Werner syndrome

Cited by 213 publications

References 33 publications

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Human Wrnip1 Is Localized in Replication Factories in a Ubiquitin-binding Zinc Finger-dependent Manner

Fibroblasts from Werner syndrome patients: Cancer cells derived by experimental introduction of oncogenes maintain malignant properties despite entering crisis

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