| 26959889 | Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer |
| 26959889 | Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence |
| 26959889 | However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells |
| 26959889 | The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells |
| 26959889 | In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis |
| 26959889 | Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens |
| 26160351 | Although WRN plays a role in DNA repair, WRN exerted its effects on aging via maintaining heterochromatin, evidenced by reduced levels of interacting chromatin regulators heterochromatin protein 1alpha (HP1alpha), suppressor of variegation 3-9 homolog 1 (SUV39H1), and lamina-associated polypeptide 2beta (LAP2beta) as well as modified histone H3K9me3 |
| 26160351 | Reducing expression of chromatin modeling co-factors SUV39H1 or HP1alpha in wild-type MSCs recapitulates the phenotype of WRN deficiency, resulting in reduced H3K9me3 levels and increased senescence without induction of markers of DNA damage, suggesting that chromatin disorganization and not DNA damage is responsible for the pathology of WS during aging in animals |
| 25931448 | Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency |
| 25931448 | We show that WRN associates with heterochromatin proteins SUV39H1 and HP1alpha and nuclear lamina-heterochromatin anchoring protein LAP2beta |
| 25931448 | Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals |
| 25931448 | Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging |
| 24832598 | We first systematically investigated whether depletion of RECQL4 and the other four human RecQ helicases, BLM, WRN, RECQL1 and RECQL5, impacts the proliferative potential of human primary fibroblasts |
| 24832598 | BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated beta-galactosidase (SA-beta-gal), higher expression of p16(INK4a) or/and p21(WAF1) and accumulated persistent DNA damage foci |
| 24747221 | Acrolein decreased Werner's syndrome protein (WRN), a member of the RecQ helicase family involved in DNA repair and telomere maintenance |
| 24747221 | Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition |
| 24747221 | CONCLUSIONS: These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein down-regulation |
| 24626990 | We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn(-/-)), telomerase (Terc(-/-)) and Wrn(-/-)Terc(-/-) double mutants |
| 24626990 | Except in the Wrn(-/-) single mutant, osteoclast number did not increase in any genotype |
| 24626809 | Werner syndrome protein positively regulates XRCC4-like factor transcription |
| 24626809 | Mutations in the WRN gene results in the development of Werner syndrome (WS), a rare autosomal recessive disorder characterized by premature ageing and genome instability |
| 24626809 | Depletion of WRN in HeLa cells led to a decrease of XLF mRNA and its promoter activity |
| 24626809 | Chromatin immunoprecipitation assays demonstrated that WRN was associated with the XLF promoter |
| 24626809 | Taken together, the results suggest that XLF is a transcriptional target of WRN and may be involved in the regulation of cellular senescence |
| 24356923 | This perspective review focused on the Werner syndrome (WS) by addressing the issue of how a single mutation in a WRN gene encoding WRN DNA helicase induces a wide range of premature aging phenotypes accompanied by an abnormal pattern of tumors |
| 24356923 | The key event caused by WRN gene mutation is the dysfunction of telomeres |
| 24356923 | As an analogy of the mechanism in natural aging, we described a hypothetical mechanism of premature aging in WS: telomere dysfunction induced by WRN mutation causes multiple premature aging phenotypes of WS, including shortened cellular lifespan and inflammation induced by ROS, such as diabetes mellitus |
| 24356923 | Thus, the majority of wide and complex pathological phenotypes of WS may be explained in a unified manner by the cascade beginning with telomere dysfunction initiated by WRN gene mutation |
| 23933816 | Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death |
| 23933816 | Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts |
| 23933816 | Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss |
| 23933816 | Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence |
| 23849162 | We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase |
| 23849162 | We observed biallelic WRN null mutations in both women (p |
| 23683351 | Oxidative DNA damage induces telomeric instability and cellular senescence that are associated with normal aging and segmental premature aging disorders such as Werner Syndrome and Rothmund-Thomson Syndrome, caused by mutations in WRN and RECQL4 helicases respectively |
| 23683351 | Characterizing the metabolic roles of RECQL4 and WRN in telomere maintenance is crucial in understanding the pathogenesis of their associated disorders |
| 23683351 | We have previously shown that WRN and RECQL4 display a preference in vitro to unwind telomeric DNA substrates containing the oxidative lesion 8-oxoguanine |
| 23683351 | Unlike that reported for telomeric D-loops containing 8-oxoguanine, RECQL4 does not cooperate with WRN to unwind telomeric D-loops with thymine glycol, suggesting RECQL4 helicase is selective for the type of oxidative lesion |
| 22754337 | In this study, we crossed Wrn(-/-) and p16(Ink4a-/-) mice to knock out the p16(Ink4a) function in a Wrn null background |
| 22754337 | Growth curves showed that loss of p16(Ink4a) could rescue the growth barriers that are observed in Wrn(-/-) mouse embryonic fibroblasts (MEFs) |
| 22754337 | By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16(Ink4a) did not dramatically affect the global DNA damage response of Wrn(-/-) MEFs induced by doxorubicin |
| 22754337 | However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2(DeltaBDeltaM), loss of p16(Ink4a) could partially overcome the DNA damage response by disabling p16(Ink4a) up-regulation and reducing the accumulation of gamma-H2AX that is observed in Wrn(-/-) MEFs |
| 22754337 | Furthermore, in response to TRF2(DeltaBDeltaM) overexpression, Wrn(-/-) MEFs senesced within several passages |
| 22621437 | Using mouse models of disrupted telomere maintenance molecules, including mutants in the Werner helicase (Wrn(-/-) ), telomerase (Terc(-/-) ), and Wrn(-/-) Terc(-/-) double mutants predisposed to accelerated bone loss, we measured telomere dysfunction-induced foci (TIFs) and markers of osteoblast differentiation in mesenchymal progenitor cells (MPCs) |
| 22301954 | MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency |
| 22301954 | To determine whether WRN deficiency impairs MYC-driven tumor development, we used both xenograft and autochthonous tumor models |
| 22301954 | Conditional silencing of WRN expression in c-MYC overexpressing non-small cell lung cancer xenografts impaired both tumor establishment and tumor growth |
| 22301954 | This inhibitory effect of WRN knockdown was accompanied by increased DNA damage, decreased proliferation, and tumor necrosis |
| 22301954 | In the Emu-Myc mouse model of B-cell lymphoma, a germline mutation in the helicase domain of Wrn (Wrn(Deltahel/Deltahel)) resulted in a significant delay in emergence of lethal lymphomas, extending tumor-free survival by more than 30% |
| 22301954 | Analysis of preneoplastic B cells from Emu-Myc Wrn mutant mice revealed increased DNA damage, elevation of senescence markers, and decreased proliferation in comparison with cells from age-matched Emu-Myc mice |
| 22301954 | Collectively, these studies show that in the context of Myc-associated tumorigenesis, loss of Wrn amplifies the DNA damage response, both in preneoplastic and neoplastic tissue, engaging activation of tumor suppressor pathways |
| 22301954 | Targeting WRN or its enzymatic function could prove to be an effective strategy in the treatment of MYC-associated cancers |
| 21365542 | Werner's Syndrome (WS) or adult-onset progeria is an autosomal recessive disorder of accelerated aging caused by mutations of the DNA RecQ helicase/exonuclease (WRN) |
| 21365542 | WRN is an ATP-dependent helicase with 3' to 5' DNA exonuclease activity that regulates the replicative potential of dividing cells, and WRN loss-of-function mutations promote cellular senescence and neoplastic transformation |
| 21365542 | Recently, a patient with WS who developed pancreatic adenocarcinoma was identified in Honolulu suggesting a significant prevalence of loss-of-function WRN mutations in Hawaii's Japanese-American population |
| 21365542 | Based upon the indigenous Japanese WRN loss-of-function mutation heterozygote rate of 6 per 1,000, we speculate the possibility of approximately 1,200 heterozygotes in Hawaii |
| 21365542 | Our ongoing studies aim to evaluate Hawaii's true allelic prevalence of WRN loss-of-function mutations in the Japanese-American population, and the role of WRN silencing in sporadic cancers |
| 21365542 | In summary, WRN plays a nexus-like role in the complex interplay of cellular events that regulate aging, and analysis of WRN polymorphisms in Hawaii's population will generate novel insights to advance care for age-related pathologies |
| 20819672 | Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants |
| 20818171 | Additional cellular activities have been identified that suppress Myc-induced senescence, including the Wrn helicase, Telomerase and Miz1 |
| 20798040 | Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes |
| 20043098 | Werner syndrome (WS) results from defects in the gene encoding WRN RecQ helicase |
| 20043098 | 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 |
| 20021393 | In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome |
| 20010815 | However, unlike loss of Wrn, loss of Cdk2 did not enhance Myc-induced replication stress, implying that these proteins suppress senescence through different routes |
| 19442255 | It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited |
| 18337721 | At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome |
| 18212065 | WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening |
| 18212065 | Our data show that the TRF2(DeltaB)-induced telomeric-loop homologous-recombination pathway requires WRN helicase |
| 18212065 | In addition, we show that WRN represses the formation of spontaneous telomeric circles, as demonstrated by the increased levels of telomeric circles observed in telomerase-positive WS fibroblasts |
| 18212065 | Circle formation in WS cells is reduced by reconstitution with wild-type WRN but not mutant forms lacking either exonuclease or helicase activity, demonstrating that both enzymatic activities of WRN are required to suppress telomeric-circle formation in normal cells expressing telomerase reverse transcriptase |
| 18212065 | Thus, WRN has a key protective function at telomeres which influences telomere topology and inhibits accelerated attrition of telomeres |
| 18203716 | Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition caused by mutations of the WRN gene |
| 18203716 | WRN is a member of the RecQ DNA helicase family with functions in maintaining genome stability |
| 18203716 | Here we show that SIRT1 interacts with WRN both in vitro and in vivo; this interaction is enhanced after DNA damage |
| 18203716 | WRN acetylation decreases its helicase and exonuclease activities, and SIRT1 can reverse this effect |
| 18203716 | WRN acetylation alters its nuclear distribution |
| 18203716 | Down-regulation of SIRT1 reduces WRN translocation from nucleoplasm to nucleoli after DNA damage |
| 18203716 | These results suggest that SIRT1 regulates WRN-mediated cellular responses to DNA damage through deacetylation of WRN |
| 18083760 | Therefore, we summarize and discuss here that (i) systemic administration of anti-cancer chemotherapeutics, in many cases DNA cross-linking drugs, induces premature progeroid frailty in long-term survivors; (ii) that ICL-inducing 8-methoxy-psoralen/UVA phototherapy leads to signs of premature skin aging as prominent long-term side effect and (iii) that mutated factors involved in ICL repair like ERCC1/XPF, the Fanconi anaemia proteins, WRN and SNEV lead to reduced replicative life span in vitro and segmental progeroid syndromes in vivo |
| 17996922 | Expression and localization of Werner syndrome protein is modulated by SIRT1 and PML |
| 17996922 | Mutations in genes for WRN and BLM RecQ family helicases cause cancer prone syndromes |
| 17996922 | Werner syndrome, resulting from WRN mutation, is a segmental progeria |
| 17996922 | Endogenous WRN and BLM proteins localize in nucleoli and in nuclear PML bodies defined by isoforms of the PML protein, which is a key regulator of cellular senescence |
| 17996922 | We further characterized WRN and BLM localization using labeling with monomeric red fluorescence protein (mRFP) |
| 17996922 | When ectopically expressed, mRFP-WRN (or untagged WRN) forms nuclear bodies, which are donut-shaped in some cells |
| 17996922 | Moreover, increased SIRT1 expression was associated with the downregulation of endogenous WRN and a decreased frequency of cells with BRCA1 foci |
| 17996922 | Our data indicate for the first time that SIRT1 protein may be functionally associated with WRN and BLM helicases and that some major SIRT1 functions may not require its deacetylase activity |
| 17321898 | Since Werner (WRN) and Bloom (BLM) helicases are crucial in cell repair and aging, their peripheral blood mononuclear cells (PBMC) mRNA levels were compared in HIV-1 infected patients and in normal donors |
| 17321898 | The mean levels of WRN mRNA were 3 |
| 17321898 | WRN increase was positively correlated to CD4 and CD8 T-cell numbers, and also the percentage of naive T lymphocytes, and was observed also in T-cell subsets |
| 17321898 | Interestingly, a general trend toward increased WRN mRNA levels in individuals with lower viral load was observed, without association with patient age, time of seroconversion, and on/off antiretroviral therapy regimen |
| 17321898 | On the whole, this study shows that WRN and BLM are differentially modulated in HIV infection, as WRN--but not BLM--is significantly increased, suggesting that mechanisms different from defect or loss of helicase function, observed in WRN and BLM syndromes, may be at the basis of T-cell aging in HIV infection |
| 17314245 | WRN at telomeres: implications for aging and cancer |
| 17314245 | The protein mutated in WS, WRN, appears to play a major role in genome stability, particularly during DNA replication and telomere metabolism |
| 17314245 | Recent genetic evidence from the mTerc(-/-) Wrn(-/-) mouse demonstrates that mice with critically shortened telomeres display aging phenotypes reminiscent of human WS, further reinforcing the notion that telomere dysfunction is required for the manifestation of aging pathophysiologies in the setting of WRN deficiency |
| 17070654 | WRN could involve DNA replication initiation, replication foci establishment, and the resolution of stalled replication forks during replication |
| 16720342 | Werner syndrome is a segmental progeroid disease characterized by increased cancer and acceleration of specific age-related phenotypes, due to loss of a protein known as WRN |
| 16720342 | Extensive research over the last decade has revealed much about WRN biochemistry and the etiology of Werner syndrome |
| 16720342 | WRN possesses multiple DNA-dependent enzymatic activities (ATPase, helicase, exonuclease, and strand annealing) and interacts with factors having established roles in DNA metabolic pathways |
| 16720342 | Although the exact functions of WRN remain unclear, accumulating evidence points to roles in proper resolution of replication blockage and in telomere maintenance |
| 16720342 | If WRN function is lost (as exemplified in cells from Werner patients), problems with replication and DNA damage processing arise, probably resulting in an increased number or persistence of strand breaks |
| 16287861 | Werner syndrome, caused by mutations of the WRN gene, mimics many changes of normal aging |
| 16287861 | Although roles for WRN protein in DNA replication, recombination, and telomere maintenance have been suggested, the pathology of rapidly dividing cells is not a feature of Werner syndrome |
| 16287861 | To identify cellular events that are specifically vulnerable to WRN deficiency, we used RNA interference (RNAi) to knockdown WRN or BLM (the RecQ helicase mutated in Bloom syndrome) expression in primary human fibroblasts |
| 16287861 | Withdrawal of WRN or BLM produced accelerated cellular senescence phenotype and DNA damage response in normal fibroblasts, as evidenced by induction of gammaH2AX and 53BP1 nuclear foci |
| 16287861 | After WRN depletion, the induction of these foci was seen most prominently in nondividing cells |
| 16287861 | These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo |
| 15336909 | The Werner syndrome protein at the crossroads of DNA repair and apoptosis |
| 15336909 | WS is caused by mutations in a gene encoding for a 160 kDa nuclear protein, the Werner syndrome protein (WRN), which has exonuclease and helicase activities |
| 15336909 | The mechanism whereby WRN controls genome stability and life span is not known |
| 15336909 | Over the last few years, WRN has become the focus of intense investigation by a growing number of scientists |
| 15336909 | The studies carried out by many laboratories have provided a wealth of new information about the functional properties of WRN and its cellular partners |
| 15336909 | This review focuses on recent findings that demonstrate a functional interaction between WRN and two factors that bind to DNA breaks, Ku and poly(ADP-ribose) polymerase 1, and discuss how these interactions can influence fundamental cellular processes such as DNA repair, apoptosis and possibly regulate cell senescence and organismal aging |
| 12842909 | Werner syndrome protein limits MYC-induced cellular senescence |
| 12842909 | Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene, WRN, which encodes a conserved RecQ helicase |
| 12842909 | Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence |
| 12842909 | The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed by hTERT expression |
| 12842909 | We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence |
| 12633936 | Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA |
| 12633936 | The best model system to date for studying human cellular ageing is the progeroid Werner's syndrome (WS), caused by a defect in WRN, a recQ-like helicase that also possesses exonuclease activity |
| 12633936 | In this paper, we characterise the interaction between WRN and an essential replication factor, PCNA |
| 12633936 | We show that wild-type WRN protein physically associates with PCNA at physiological protein concentrations in normal cells, while no association is seen in cells from patients with WS |
| 12633936 | We demonstrate co-localisation of WRN and PCNA at replication factories, show that PCNA binds to two distinct functional sites on WRN, and suggest a mechanism by which association between WRN and PCNA may be regulated in cells on DNA damage and during DNA replication |
| 11389927 | The Saccharomyces cerevisiae SGS1 gene is a member of the RecQ family of ATP-dependent DNA helicases, which includes the human WRN, BLM and RECQ4 genes |
| 11389927 | Mutations in the WRN gene cause the human premature ageing disorder, Werner's syndrome |
| 9774636 | The regulation of Werner's syndrome gene (WRN) expression was studied by characterizing the cis-regulatory elements in the promoter region and the trans-activating factors that bind to them |
| 9774636 | A region consisting of nucleotides -67 to +160 was identified as the principal promoter of WRN by reporter gene assays in HeLa cells, using a series of WRN promoter-luciferase reporter (WRN-Luc) plasmids that contained the 5'-truncated or mutated WRN upstream regions |
| 9774636 | The RCE enhances WRN promoter activity |
| 9774636 | Coexpression of the WRN-Luc plasmids with various dosages of plasmids expressing Rb or p53 in Saos2 cells lacking active Rb and p53 proteins showed that the introduced Rb upregulates WRN promoter activity a maximum of 2 |
| 9774636 | Consistently, the overexpressed Rb and p53 proteins also affected the endogenous WRN mRNA levels in Saos2 cells, resulting in an increase with Rb and a decrease with p53 |
| 9271578 | The SGS1 gene of yeast encodes a DNA helicase with homology to the human WRN gene |
| 9271578 | Mutations in WRN result in Werner's syndrome, a disease with symptoms resembling premature aging |
| 7822435 | The Werner syndrome (WS) is a segmental progeroid syndrome caused by a recessive mutation (WRN) mapped to 8p12 |
