The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases

Shen, Jiang; Loeb, Lawrence A.

doi:10.1016/s0168-9525(99)01970-8

Cited by 163 publications

(113 citation statements)

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“…Biochemical analyses of WRN action on defined oligonucleotide substrates indicate that the biochemical activities of WRN can compete to unwind or degrade different templates, and that the outcome is determined by a combination of substrate conformation, the balance of WRN catalytic activities and the presence of additional proteins that have been shown to interact with WRN (reviewed in [9,10]). For example, the requirement for both WRN catalytic activities in recombination may reflect the ability of WRN and RPA to efficiently unwind strand invasion intermediates such as D-loops [34].…”

Section: Discussionmentioning

confidence: 99%

“…6B and C) [33,35]. Each pathway is plausible in light of known biochemical properties and actions of the WRN catalytic activities in vitro (reviewed in [9,10]). Additional biochemical requirements in each of the above survival pathways could be fulfilled by RecQ helicases, topoisomerases, or replication and recombination proteins that have been shown to interact with WRN [7,10].…”

Section: Discussionmentioning

confidence: 99%

“…Biochemical characterization of the human WRN RecQ helicase protein has revealed a unique 3 to 5 exonuclease activity in addition to the 3 to 5 helicase and ATPase activities characteristic of other RecQ helicase proteins [9,10]. Among the WRN mutations that have been identified in WS patients, none selectively inactivates the WRN exonuclease or helicase activities [11].…”

Section: Introductionmentioning

confidence: 99%

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The Werner syndrome protein has separable recombination and survival functions☆

et al. 2004

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The Werner syndrome (WS) protein WRN is unique in possessing a 3 to 5 exonuclease activity in addition to the 3 to 5 helicase activity characteristic of other RecQ proteins. In order to determine in vivo functions of the WRN catalytic activities and their roles in Werner syndrome pathogenesis, we quantified cell survival and homologous recombination after DNA damage in cells expressing WRN missense-mutant proteins that lacked exonuclease and/or helicase activity. Both WRN biochemical activities were required to generate viable recombinant daughter cells. In contrast, either activity was sufficient to promote cell survival after DNA damage in the absence of recombination. These results indicate that WRN has recombination and survival functions that can be separated by missense mutations. Two implications are that Werner syndrome most likely results from the loss of both activities and their associated functions from patient cells, and that WRN missense mutations or polymorphisms could promote genetic instability and cancer in the general population by selectively interfering with recombination in somatic cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Werner syndrome protein has separable recombination and survival functions☆

et al. 2004

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“…Three syndromes, Bloom's syndrome, Werner's syndrome and Rothmund Á/Thomson syndrome are autosomal recessive genomic instability disorders associated with cancer predisposition and/or premature aging which involve mutations in genes encoding RecQ family helicases Á/ enzymes responsible for maintenance of genome integrity [188]. Mutations in the WRN gene give rise to Werner's syndrome, which characterized by many, but not all, of the features of the normal aging, including premature graying an thinning of the hair loss of skin elasticity, cataracts, type II diabetes mellitus, hypogonadism, osteoporosis, atherosclerosis and predisposition to malignancies, mainly to sarcomas [189]. Bloom's syndrome, a rare disorder associated with the BLM gene mutation and pleiotropic phenotypes including immunodeficiency, impaired fertility, proportional dwarfism, sun-induced facial erythematic, and early development of cancers of all types [190].…”

Section: Do Premature Aging Promote Carcinogenesis?mentioning

confidence: 99%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by several mechanisms: (1) tissue accumulation of cells in late stages of carcinogenesis; (2) alterations in homeostasis, in particular, alterations in immune and endocrine system and (3) telomere instability linking aging and increased cancer risk. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Available evidence supporting the relevance of replicative senescence of human cells and telomere biology to human cancer seems quite strong, however, the evidence linking cellular senescence to human aging is controversial and required additional stuidies. Data on the acceleration of aging by carcinogenic agents as well as on increased cancer risk in patients with

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“…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). More recently, models were proposed to explain WRN function in replication restart and/or recombinational repair after replication fork stalling (Chakraverty and Hickson, 1999;Shen and Loeb, 2000), also cooperating with RAD51, a key enzyme in homologous recombination (HR) (reviewed by Haber, 2000), and an activity of WRN in the translocation of Holliday junctions has been proposed (Constantinou et al, 2000). In this work, the hypothesized involvement of WRN in the restart of DNA synthesis after replication fork collapse has been further investigated, taking into consideration the proper activation of the RAD51-dependent recombinational pathway of DNA synthesis restarting.…”

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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

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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 Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases

Cited by 163 publications

References 69 publications

The Werner syndrome protein has separable recombination and survival functions☆

The Werner syndrome protein has separable recombination and survival functions☆

The relationship between aging and carcinogenesis: a critical appraisal

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

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