Редактирование: WRN

Werner syndrome ATP-dependent helicase (EC 3.6.4.12) (DNA helicase, RecQ-like type 3) (RecQ3) (Exonuclease WRN) (EC 3.1.-.-) (RecQ protein-like 2) [RECQ3] [RECQL2]

==Publications==

{{medline-entry
|title=The Impact of Vitamin C on Different System Models of Werner Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33202145
|abstract= Werner syndrome (WS) is a rare autosomal recessive malady typified by a pro-oxidant/proinflammatory status, genetic instability, and by the early onset of numerous age-associated illnesses. The protein malfunctioning in WS individuals ([[WRN]]) is a helicase/exonuclease implicated in transcription, DNA replication/repair, and telomere maintenance.   In the last two decades, a series of important biological systems were created to comprehend at the molecular level the effect of a defective [[WRN]] protein. Such biological tools include mouse and worm ([i]Caenorhabditis elegans[/i]) with a mutation in the Wrn helicase ortholog as well as human WS-induced pluripotent stem cells that can ultimately be differentiated into most cell lineages. Such WS models have identified anomalies related to the hallmarks of aging. Most importantly, vitamin C counteracts these age-related cellular phenotypes in these systems.   Vitamin C is the only antioxidant agent capable of reversing the cellular aging-related phenotypes in those biological systems. Since vitamin C is a cofactor for many hydroxylases and mono- or dioxygenase, it adds another level of complexity in deciphering the exact molecular pathways affected by this vitamin. Moreover, it is still unclear whether a short- or long-term vitamin C supplementation in human WS patients who already display aging-related phenotypes will have a beneficial impact.   The discovery of new molecular markers specific to the modified biological pathways in WS that can be used for novel imaging techniques or as blood markers will be necessary to assess the favorable effect of vitamin C supplementation in WS.

|keywords=* Werner syndrome
* aging
* mouse
* stem cells
* vitamin C
* worm
|full-text-url=https://sci-hub.do/10.1089/ars.2020.8147
}}
{{medline-entry
|title=[[WRN]] modulates translation by influencing nuclear mRNA export in HeLa cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33054770
|abstract=The Werner syndrome protein ([[WRN]]) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by [[WRN]] depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation. To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after [[WRN]] knockdown. We determined that [[WRN]] depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that [[WRN]] depletion affects the nuclear export of mRNAs and demonstrated that [[WRN]] interacts with mRNA and the Nuclear RNA Export Factor 1 ([[NXF1]]). Our findings suggest that [[WRN]] influences the export of mRNAs from the nucleus through its interaction with the [[NXF1]] export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of [[WRN]], which is especially important for the proliferation of cancer cells.

|keywords=* Cancer
* NXF1 export receptor
* Senescence
* Translation
* Werner syndrome protein
* mRNA export
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557079
}}
{{medline-entry
|title=[[MIB1]]-mediated degradation of [[WRN]] promotes cellular senescence in response to camptothecin treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32652764
|abstract=Werner syndrome protein ([[WRN]]) plays critical roles in DNA replication, recombination, and repair, as well as transcription and cellular senescence. Ubiquitination and degradation of [[WRN]] have been reported, however, the E3 ubiquitin ligase of [[WRN]] is little known. Here, we identify mindbomb E3 ubiquitin protein ligase 1 ([[MIB1]]) as a novel E3 ubiquitin ligase for [[WRN]] protein. [[MIB1]] physically interacts with [[WRN]] in vitro and in vivo and induces ubiquitination and degradation of [[WRN]] in the ubiquitin-proteasome pathway. Camptothecin (CPT) enhances the interaction between [[MIB1]] and [[WRN]], and promotes [[WRN]] degradation in a [[MIB1]]-dependent manner. In addition, CPT-induced cellular senescence is facilitated by the expression of [[MIB1]] and attenuated by [[WRN]] expression. Our results show that [[MIB1]]-mediated degradation of [[WRN]] promotes cellular senescence and reveal a novel model executed by [[MIB1]] and [[WRN]] to regulate cellular senescence.

|keywords=* CPT
* Mind bomb 1
* Werner syndrome protein
* aging
* protein stability
|full-text-url=https://sci-hub.do/10.1096/fj.202000268RRR
}}
{{medline-entry
|title=A Case Report of Werner's Syndrome With a Novel Mutation From India.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32528764
|abstract=Werner's syndrome (WS) or progeria adultorum is a heritable autosomal recessive disease in which the aging process is accelerated, just after puberty. It is caused by mutations in the [[WRN]] gene, which encodes a member of the RECQ family of DNA helicases and has a role in DNA repair. WS is being more appropriately recognized as a condition in which the lack of [[WRN]] protein results in an overall decline in the normal physiological functions of various organs rather than premature aging. Here, we describe a rare case of WS with a novel mutation from India. Our patient was an adult male with a history of growth arrest since puberty and other clinical features such as sclerodermatous skin changes, premature graying and thinning of hair, bilateral cataract, a single non-healing ulcer, hypothyroidism, underdeveloped secondary sexual characters with hypogonadism, infertility, squeaky voice, and early signs of arteriosclerosis. On genetic analysis, he was found to have a homozygous pathogenic variant c.3190C>T in exon 26 of the [[WRN]] gene, which has never been reported in WS.

|keywords=* aging
* novel mutation
* progeria
* werner syndrome
* wrn gene
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282380
}}
{{medline-entry
|title=Evidence for premature aging in a Drosophila model of Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31518666
|abstract=Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients' early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in [[WRN]], a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human [[WRN]] has both an exonuclease and helicase domain, Drosophila [[WRN]]exo has high genetic and functional homology to only the exonuclease domain of [[WRN]]. Like [[WRN]]-deficient human cells, Drosophila [[WRN]]exo null mutants ([[WRN]]exo ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, [[WRN]]exo  flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of [[WRN]]exo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging.
|mesh-terms=* Aging, Premature
* Animals
* Behavior, Animal
* Body Composition
* Body Weight
* DNA Repair
* Drosophila
* Drosophila Proteins
* Exonucleases
* Female
* Gastrointestinal Neoplasms
* Male
* Motor Activity
* Muscle Weakness
* Mutation
* Phenotype
* Werner Syndrome
|keywords=* Aging
* DNA repair
* Locomotor function
* Tumor
* Werner syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935377
}}
{{medline-entry
|title=Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31259468
|abstract=Werner Syndrome (WS) is an adult-onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 [[WRN]]-mutant) or atypical WS (3 [[LMNA]]-mutant and 3 [[POLD1]]-mutant) patients and age- and sex-matched controls. WS was not associated with either age-related accelerated global losses of ALU, LINE1, and α-satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the [[HOXA4]] promoter. Additional DMR genes included [[LMNA]], [[POLD1]], and 132 genes which have been reported to be differentially expressed in [[WRN]]-mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence-specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of [[WRN]] protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS- and age-related methylation changes exhibited a constant offset of methylation between [[WRN]]-mutant patients and controls across the entire analyzed age range. WS-specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.
|mesh-terms=* Aging
* Epigenesis, Genetic
* Humans
* Methylation
* Mutation
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* (classical and atypical) Werner syndrome
* bisulfite pyrosequencing
* methylation array
* premature aging
* segmental progeria
* transcription deficiency
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718529
}}
{{medline-entry
|title=Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30666569
|abstract=Aging is a natural and unavoidable part of life. However, aging is also the primary driver of the dominant human diseases, such as cardiovascular disease, cancer, and neurodegenerative diseases, including Alzheimer's disease. Unraveling the sophisticated molecular mechanisms of the human aging process may provide novel strategies to extend 'healthy aging' and the cure of human aging-related diseases. Werner syndrome (WS), is a heritable human premature aging disease caused by mutations in the gene encoding the Werner ([[WRN]]) DNA helicase. As a classical premature aging disease, etiological exploration of WS can shed light on the mechanisms of normal human aging and facilitate the development of interventional strategies to improve healthspan. Here, we summarize the latest progress of the molecular understandings of [[WRN]] protein, highlight the advantages of using different WS model systems, including Caenorhabditis elegans, Drosophila melanogaster and induced pluripotent stem cell (iPSC) systems. Further studies on WS will propel drug development for WS patients, and possibly also for normal age-related diseases.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Drosophila melanogaster
* Humans
* Models, Biological
* Mutation
* Werner Syndrome
|keywords=* Aging
* DNA repair
* Hallmarkers of aging
* Mitophagy
* NAD 
* Premature aging
* Werner syndrome
|full-text-url=https://sci-hub.do/10.1007/s10522-019-09798-2
}}
{{medline-entry
|title=Werner Syndrome Protein and DNA Replication.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30400178
|abstract=Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein ([[WRN]]), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3' to 5' helicase activities. [[WRN]] forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. [[WRN]] binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, [[WRN]] is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA-dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for [[WRN]] to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that [[WRN]] plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, [[WRN]] helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human [[WRN]]'s contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding [[WRN]]'s molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS.
|mesh-terms=* Animals
* DNA Repair
* DNA Replication
* Humans
* Phosphorylation
* Protein Stability
* Proteolysis
* Werner Syndrome Helicase
|keywords=* DNA double-strand repair
* Werner Syndrome
* Werner Syndrome Protein
* cancer
* post-translational modification
* premature aging
* protein stability
* replication stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274846
}}
{{medline-entry
|title=A case report of Werner's syndrome with bilateral juvenile cataracts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30107835
|abstract=To report a case of Werner's syndrome with bilateral juvenile cataracts. Review of the clinical, laboratory, photographic, genetic testing of the patient. A 26-year-old Chinese man presented with impaired vision in both eyes for more than a year. Anterior segment examination of both eyes revealed cataract. According to the ocular symptoms and systemic signs, including low body weight, a short stature, a bird-like face, atrophic and scleroderma-like skin, in addition to the juvenile cataracts, the clinical diagnosis of Werner's syndrome was made. Next-generation sequencing identified a homozygous [[WRN]] mutation in this patient. The ocular and systemic findings in this patient in combination with the homozygous [[WRN]] mutation indicated the definitive Werner's syndrome diagnosis.
|mesh-terms=* Adult
* Cataract
* Humans
* Lens, Crystalline
* Male
* Pedigree
* Photography
* Ultrasonography
* Werner Syndrome
|keywords=* Premature aging
* WRN mutation
* Werner’s syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092780
}}
{{medline-entry
|title=Genomic instability and DNA replication defects in progeroid syndromes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29936894
|abstract=Progeroid syndromes induced by mutations in lamin A or in its interactors - named progeroid laminopathies - are model systems for the dissection of the molecular pathways causing physiological and premature aging. A large amount of data, based mainly on the Hutchinson Gilford Progeria syndrome (HGPS), one of the best characterized progeroid laminopathy, has highlighted the role of lamins in multiple DNA activities, including replication, repair, chromatin organization and telomere function. On the other hand, the phenotypes generated by mutations affecting genes directly acting on DNA function, as mutations in the helicases [[WRN]] and [[BLM]] or in the polymerase polδ, share many of the traits of progeroid laminopathies. These evidences support the hypothesis of a concerted implication of DNA function and lamins in aging. We focus here on these aspects to contribute to the comprehension of the driving forces acting in progeroid syndromes and premature aging.
|mesh-terms=* Animals
* DNA
* DNA Replication
* Genomic Instability
* Humans
* Progeria
|keywords=* DNA damage
* DNA replication
* Lamin
* aging
* nuclear lamina
* progeria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000143
}}
{{medline-entry
|title=Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29908963
|abstract=Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, [[WRN]]. Mice lacking part of the helicase domain of the [[WRN]] orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter lifespan. Yet, little is known about the impact of [[WRN]] mutations on the central nervous system in both humans and mouse models of WS. In the current study, we have performed a longitudinal behavioral assessment on mice bearing a Wrn helicase deletion. Behavioral tests demonstrated a loss of motor activity and coordination, reduction in perception, increase in repetitive behavior, and deficits in both spatial and social novelty memories in Wrn mutant mice compared to age-matched wild type mice. These neurological deficits were associated with biochemical and histological changes in the brain of aged Wrn mutant mice. Microglia, resident immune cells that regulate neuronal plasticity and function in the brain, were hyper-ramified in multiple regions involved with the behavioral deficits of Wrn mutant mice. Furthermore, western analyses indicated that Wrn mutant mice exhibited an increase of oxidative stress markers in the prefrontal cortex. Supporting these findings, electron microscopy studies revealed increased cellular aging and oxidative stress features, among microglia and neurons respectively, in the prefrontal cortex of aged Wrn mutant mice. In addition, multiplex immunoassay of serum identified significant changes in the expression levels of several pro- and anti-inflammatory cytokines. Taken together, these findings indicate that microglial dysfunction and neuronal oxidative stress, associated with peripheral immune system alterations, might be important driving forces leading to abnormal neurological symptoms in WS thus suggesting potential therapeutic targets for interventions.
|mesh-terms=* Animals
* Cellular Senescence
* DNA Damage
* Disease Models, Animal
* Female
* Longitudinal Studies
* Male
* Mice
* Mice, Inbred C57BL
* Microglia
* Motor Activity
* Mutant Proteins
* Neurons
* Oxidative Stress
* Reactive Oxygen Species
* RecQ Helicases
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* Behavior
* Brain
* Cytokines
* Microglia
* Mouse aging
* Neuron
* Oxidative stress
* Werner syndrome
|full-text-url=https://sci-hub.do/10.1016/j.bbi.2018.06.007
}}
{{medline-entry
|title=Acidic domain of [[WRN]]p is critical for autophagy and up-regulates age associated proteins.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29800817
|abstract=Impaired autophagy may be associated with normal and pathological aging. Here we explore a link between autophagy and domain function of Werner protein ([[WRN]]p). Werner ([[WRN]]) mutant cell lines AG11395, AG05229 and normal aged fibroblast AG13129 display a deficient response to tunicamycin mediated endoplasmic reticulum (ER) stress induced autophagy compared to clinically unaffected GM00637 and normal young fibroblast GM03440. Cellular endoplasmic reticulum (ER) stress mediated autophagy in WS and normal aged cells is restored after transfection with wild type full length [[WRN]], but deletion of the acidic domain from wild type [[WRN]] fails to restore autophagy. The acidic domain of [[WRN]]p was shown to regulate its transcriptional activity, and here, we show that it affects the transcription of certain proteins involved in autophagy and aging. Furthermore, siRNA mediated silencing of [[WRN]] in normal fibroblast WI-38 resulted in decrease of age related proteins Lamin A/C and Mre11.
|mesh-terms=* Adolescent
* Adult
* Aged, 80 and over
* Autophagy
* Cell Line
* Endoplasmic Reticulum Stress
* Female
* Gene Expression Regulation
* Humans
* Lamins
* MRE11 Homologue Protein
* Male
* Middle Aged
* Mutation
* Protein Domains
* Up-Regulation
* Werner Syndrome
* Werner Syndrome Helicase
* Young Adult
|keywords=* Acidic domain
* Aging
* Autophagy
* Beclin-1
* Endoplasmic reticulum
* RecQ helicase
* Werner protein
* Werner syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338341
}}
{{medline-entry
|title=RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29752965
|abstract=Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene [[WRN]], and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene [[LMNA]] that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome. The RecQ disorders Cockayne syndrome and xeroderma pigmentosum result from disease-causing DNA sequence variants in genes involved in the nucleotide excision repair pathway. RECQ2018: The International Meeting on RECQ Helicases and Related Diseases was held on February 16-18, 2018 in Chiba, Japan. The purpose of the meeting was to facilitate clinical and research collaborations for the goal of developing effective treatments for RECQ disorders and other progeroid syndromes.
|mesh-terms=* Animals
* Cockayne Syndrome
* Congresses as Topic
* DNA Repair
* DNA Repair-Deficiency Disorders
* Humans
* Japan
* Werner Syndrome Helicase
|keywords=* Aging
* Genomic instability
* Progeroid syndrome
* RECQ2018
* Werner syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217841
}}
{{medline-entry
|title=Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29476423
|abstract=Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A ([[LMNA]]) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in [[WRN]] gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/ ) or homozygous (G608G/G608G) [[LMNA]] mutation and biallelic [[WRN]] knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
|mesh-terms=* Aging
* DNA Helicases
* Human Embryonic Stem Cells
* Humans
* Kinetics
* Lamin Type A
* Mesenchymal Stem Cells
* Mutation
* Progeria
* Werner Syndrome
|keywords=* HGPS
* WRN
* Werner syndrome
* aging
* lamin
* stem cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876188
}}
{{medline-entry
|title=Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant [[WRN]] protein.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29452565
|abstract=Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase ([[WRN]]). Mice lacking part of the helicase domain of the [[WRN]] ortholog exhibit several phenotypic features of WS. In this study, we generated a Wrn mutant line that, like humans, relies entirely on dietary sources of vitamin C (ascorbate) to survive, by crossing them to mice that lack the gulonolactone oxidase enzyme required for ascorbate synthesis. In the presence of 0.01% ascorbate (w/v) in drinking water, double-mutant mice exhibited a severe reduction in lifespan, small size, sterility, osteopenia, and metabolic profiles different from wild-type (WT) mice. Although increasing the dose of ascorbate to 0.4% improved dramatically the phenotypes of double-mutant mice, the metabolic and cytokine profiles were different from age-matched WT mice. Finally, double-mutant mice treated with 0.01% ascorbate revealed a permanent activation of all the 3 branches of the ER stress response pathways due to a severe chronic oxidative stress in the ER compartment. In addition, markers associated with the ubiquitin-proteasome-dependent ER-associated degradation pathway were increased. Augmenting the dose of ascorbate reversed the activation of this pathway to WT levels rendering this pathway a potential therapeutic target in WS.-Aumailley, L., Dubois, M. J., Brennan, T. A., Garand, C., Paquet, E. R., Pignolo, R. J., Marette, A., Lebel, M. Serum vitamin C levels modulate the lifespan and endoplasmic reticulum stress response pathways in mice synthesizing a nonfunctional mutant [[WRN]] protein.
|mesh-terms=* Animals
* Ascorbic Acid
* Endoplasmic Reticulum Stress
* Female
* Longevity
* Loss of Function Mutation
* Male
* Mice
* Mice, Inbred C57BL
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* Werner syndrome
* aging
* ascorbate
* gulonolactone oxidase
* metabolomic
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998970
}}
{{medline-entry
|title=Werner syndrome ([[WRN]]) gene variants and their association with altered function and age-associated diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29146545
|abstract=Werner syndrome (WS) is a heritable autosomal recessive human disorder characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients, [[WRN]], is encoded by a member of the human RECQ gene family that contains both a DNA exonuclease and a helicase domain. [[WRN]] has been shown to participate in several DNA metabolic pathways including DNA replication, recombination and repair, as well as telomere maintenance and transcription modulation. Here we review base pair-level genetic variation that has been documented in [[WRN]], with an emphasis on non-synonymous coding single nucleotide polymorphisms (SNPs) and their associations with anthropomorphic features, longevity and disease risk. These associations have been challenging to identify, as many reported [[WRN]] SNP associations appear to be further conditioned upon ethnic, age, gender or other environmental co-variables. The [[WRN]] variant phenotypic associations identified to date are intriguing, and several are of clear clinical import. Consequently, it will be important to extend these initial associations and to identify the mechanisms and conditions under which specific [[WRN]] variants may compromise [[WRN]] function to drive cellular and organismal phenotypes as well as disease risk.
|mesh-terms=* Aging
* Animals
* DNA Repair
* DNA Replication
* Exodeoxyribonucleases
* Genetic Association Studies
* Genetic Variation
* Humans
* Neoplasms
* RecQ Helicases
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* Age-related phenotypes
* Cancer
* Longevity
* Single nucleotide polymorphisms
* Werner syndrome
|full-text-url=https://sci-hub.do/10.1016/j.arr.2017.11.003
}}
{{medline-entry
|title=Human RecQL4 helicase plays multifaceted roles in the genomic stability of normal and cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29080750
|abstract=Human RecQ helicases that share homology with E. coli RecQ helicase play critical roles in diverse biological activities such as DNA replication, transcription, recombination and repair. Mutations in three of the five human RecQ helicases (RecQ1, [[WRN]], [[BLM]], RecQL4 and RecQ5) result in autosomal recessive syndromes characterized by accelerated aging symptoms and cancer incidence. Mutational inactivation of Werner ([[WRN]]) and Bloom ([[BLM]]) genes results in Werner syndrome (WS) and Bloom syndrome (BS) respectively. However, mutations in RecQL4 result in three human disorders: (I) Rothmund-Thomson syndrome (RTS), (II) RAPADILINO and (III) Baller-Gerold syndrome (BGS). Cells from WS, BS and RTS are characterized by a unique chromosomal anomaly indicating that each of the RecQ helicases performs specialized function(s) in a non-redundant manner. Elucidating the biological functions of RecQ helicases will enable us to understand not only the aging process but also to determine the cause for age-associated human diseases. Recent biochemical and molecular studies have given new insights into the multifaceted roles of RecQL4 that range from genomic stability to carcinogenesis and beyond. This review summarizes some of the existing and emerging knowledge on diverse biological functions of RecQL4 and its significance as a potential molecular target for cancer therapy.
|mesh-terms=* Anal Canal
* Antineoplastic Agents
* Biomarkers, Tumor
* Cell Proliferation
* Cell Transformation, Neoplastic
* Craniosynostoses
* DNA Repair
* DNA Replication
* DNA, Mitochondrial
* Dwarfism
* Enzyme Inhibitors
* Genetic Predisposition to Disease
* Genomic Instability
* Heart Septal Defects, Atrial
* Humans
* Limb Deformities, Congenital
* Mutation
* Neoplasms
* Patella
* Phenotype
* Radius
* RecQ Helicases
* Rothmund-Thomson Syndrome
|keywords=* Aneuploidy
* Cancer
* DNA replication
* Mitotic checkpoint
* Premature aging syndromes
* RecQ helicases
|full-text-url=https://sci-hub.do/10.1016/j.canlet.2017.10.021
}}
{{medline-entry
|title=Recent Advances in Understanding Werner Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29043077
|abstract=Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. [[WRN]], being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated [[WRN]]'s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

|keywords=* Aging
* DSB repair
* Senescence
* Telomere maintenance
* WRN
* Werner Syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621106
}}
{{medline-entry
|title=Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28934497
|abstract=DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. [[XPA]]-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan. Compensatory roles for global-genome (XPC-1) and transcription-coupled (CSB-1) NER in ICL sensing were exposed. The analysis also revealed contributions of homologous recombination (BRC-1/BRCA1), the MUS-81, EXO-1, SLX-1 and FAN-1 nucleases, and the DOG-1 (FANCJ) helicase in ICL resolution, influenced by the replicative-status of the cell/tissue. No obvious or critical role in ICL repair was seen for non-homologous end-joining (cku-80) or base excision repair (nth-1, exo-3), the Fanconi-related proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2), the [[WRN]]-1 or HIM-6 (BLM) helicases, or the GEN-1 or MRT-1 (SNM1) nucleases. Our efforts uncover replication-dependent and -independent ICL repair networks, and establish nematodes as a model for investigating the repair and consequences of DNA crosslinks in metazoan development and in adult post-mitotic and proliferative germ cells.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* DNA
* DNA Repair
* Female
* Homologous Recombination
* Male
* Mutation
* Trioxsalen
* Ultraviolet Rays

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766164
}}
{{medline-entry
|title=The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and [[FEN1]]-Mediated Flap Cleavage during Polymerase δ Elongation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27849570
|abstract=The Werner syndrome protein ([[WRN]]) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either [[WRN]] or the Bloom syndrome helicase (BLM) stimulates DNA polymerase δ progression across telomeric G-rich repeats, only [[WRN]] promotes sequential strand displacement synthesis and [[FEN1]] cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity, as well as the conserved winged-helix (WH) motif and the helicase and RNase D C-terminal (HRDC) domain play important but distinct roles in this process. Remarkably, [[WRN]] also influences the formation of [[FEN1]] cleavage products during strand displacement on a nontelomeric substrate, suggesting that [[WRN]] recruitment and cooperative interaction with [[FEN1]] during lagging-strand synthesis may serve to regulate sequential strand displacement and flap cleavage at other genomic sites. These findings define a biochemical context for the physiological role of [[WRN]] in maintaining genetic stability.
|mesh-terms=* Amino Acid Motifs
* DNA
* DNA Polymerase III
* DNA Replication
* Flap Endonucleases
* HeLa Cells
* Homeostasis
* Humans
* Polymerization
* Protein Domains
* RecQ Helicases
* Repetitive Sequences, Nucleic Acid
* Substrate Specificity
* Telomere
* Werner Syndrome Helicase
|keywords=* DNA helicase
* DNA replication
* Okazaki fragment
* Werner syndrome
* aging
* lagging strand
* lagging-strand synthesis
* telomeres
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247617
}}
{{medline-entry
|title=Vitamin C alleviates aging defects in a stem cell model for Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27271327
|abstract=Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using [[WRN]]-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in [[WRN]]-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in [[WRN]]-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.
|mesh-terms=* Animals
* Ascorbic Acid
* Cell Cycle Checkpoints
* Cell Line
* Cellular Senescence
* DNA Damage
* DNA Repair
* DNA Replication
* Disease Models, Animal
* Heterochromatin
* Humans
* Mesenchymal Stem Cells
* Mice
* Nuclear Lamina
* Reactive Oxygen Species
* Telomere Homeostasis
* Werner Syndrome
|keywords=* Vitamin C
* Werner syndrome
* aging
* stem cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930768
}}
{{medline-entry
|title=Bloom's syndrome: Why not premature aging?: A comparison of the [[BLM]] and [[WRN]] helicases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27238185
|abstract=Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - [[BLM]], [[WRN]], and [[RECQL4]] - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The [[BLM]] helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.
|mesh-terms=* Aging
* Aging, Premature
* Bloom Syndrome
* DNA Helicases
* DNA Replication
* Genomic Instability
* Humans
* Mutation
* RecQ Helicases
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* Aging
* BLM
* Bloom’s syndrome
* Cancer susceptibility
* Genomic instability
* RecQ helicases
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124422
}}
{{medline-entry
|title=Understanding Vascular Diseases: Lessons From Premature Aging Syndromes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26948039
|abstract=Early human mummies examined recently by computed tomography demonstrated a high prevalence of vascular calcification, a pathognomonic sign of atherosclerosis, which was correlated with estimated age at death. Early populations had little exposure to modern-day metabolic risk factors: these observations thus suggest that humans have an inherent age-dependent predisposition to atherosclerosis. Premature aging syndromes are extremely rare genetic disorders that exhibit clinical phenotypes resembling accelerated aging, including severe atherosclerosis, but those phenotypes are usually segmental. Controversy persists, therefore, regarding the extent to which the molecular mechanisms underlying premature aging syndromes overlap with those of physiological aging. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome are well-characterized premature aging syndromes. HGPS is caused by gain-of-function mutations in the [[LMNA]] gene, which result in the accumulation of a mutant nuclear protein, called "progerin," at the nuclear rim. In contrast, loss-of-function mutations in Werner syndrome ATP-dependent helicase ([[WRN]]) lead to Werner syndrome. Mesenchymal stem cells (MSCs), which can differentiate into vascular cells to maintain vascular homeostasis in response to injury, are severely affected in these syndromes. Mechanistically, either aberrant expression of progerin or loss of [[WRN]] protein in MSCs alters heterochromatin structure, resulting in premature senescence and exhaustion of functional MSCs in premature aging syndromes. Surprisingly, vascular cells and MSCs in elderly healthy individuals have shown progerin expression and decreased expression levels of [[WRN]], respectively. Studying these rare genetic disorders could thus provide valuable insights into age-related vascular diseases that occur in the general population. 
|mesh-terms=* Aging
* Aging, Premature
* Atherosclerosis
* Humans
* Lamin Type A
* Mummies
* Mutation
* Phenotype
* Progeria
* Werner Syndrome

|full-text-url=https://sci-hub.do/10.1016/j.cjca.2015.12.003
}}
{{medline-entry
|title=Stem Cell Depletion by Global Disorganization of the H3K9me3 Epigenetic Marker in Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26160351
|abstract=Epigenomic change and stem cell exhaustion are two of the hallmarks of aging. Accumulation of molecular damage is thought to underlie aging, but the precise molecular composition of the damage remains controversial. That some aging phenotypes, especially those that result from impaired stem cell function, are reversible suggest that such "damage" is repairable. Evidence is accumulating that dysfunction in aging stem cells results from increasing, albeit, subtle disorganization of the epigenome over time. Zhang et al. (2015) report that decreasing levels of [[WRN]], Werner's syndrome (WS) helicase, with increasing age results in loss of heterochromatin marks in mesenchymal stem cells (MSCs) and correlates with an increased rate of cellular senescence. 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 1α (HP1α), suppressor of variegation 3-9 homolog 1 ([[SUV39H1]]), and lamina-associated polypeptide 2β (LAP2β) as well as modified histone H3K9me3. Reducing expression of chromatin modeling co-factors [[SUV39H1]] or HP1α 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. Ectopic expression of HP1α restored H3K9me3 levels and repressed senescence in [[WRN]]-deficient MSCs. That HP1α can also suppress senescence in Hutchinson-Gilford progeria syndrome (HGPS) and extend life span in flies when over-expressed suggests that HP1α and H3K9me3 play conserved roles in maintenance of cell state. H3K9me3 levels are dynamic and expected to be potentially responsive to manipulation by extrinsic factors. Recent reports that migration inhibitory factor (MIF) or periodic fasting rejuvenate old MSCs provide the opportunity to link intrinsic and extrinsic mechanisms of aging in novel and potentially medically important ways and may lead to anti-aging treatments that reorganize the epigenome to rejuvenate cells and tissues. 
|mesh-terms=* Aging
* Animals
* Biomarkers
* Epigenesis, Genetic
* Histones
* Humans
* Lysine
* Methylation
* Stem Cells

|full-text-url=https://sci-hub.do/10.1089/rej.2015.1742
}}
{{medline-entry
|title=The Werner Protein Acts as a Coactivator of Nuclear Factor κB (NF-κB) on HIV-1 and Interleukin-8 (IL-8) Promoters.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26037922
|abstract=The Werner syndrome helicase ([[WRN]]) plays a role in maintaining genomic stability. The lack of [[WRN]] results in Werner syndrome, a rare autosomal recessive genetic disorder, which causes premature aging accompanied by many complications such as rare forms of cancer and type 2 diabetes. However, the underlying mechanisms of these complications, arising due to the loss of [[WRN]], are poorly understood. In this study, we demonstrated the function of [[WRN]] in transcriptional regulation of NF-κB targets. [[WRN]] physically interacts via its RecQ C-terminal (RQC) domain with the Rel homology domain of both the RelA (p65) and the p50 subunits of NF-κB. In the steady state, [[WRN]] is recruited to HIV-1 long terminal repeat (LTR), a typical NF-κB-responsive promoter, as well as the p50/p50 homodimer, in an NF-κB site-dependent manner. The amount of [[WRN]] on LTR increased along with the transactivating RelA/p50 heterodimer in response to [[TNF]]-α stimulation. Further, a knockdown of [[WRN]] reduced the transactivation of LTR in exogenous RelA/p50-introduced or [[TNF]]-α-stimulated cells. Additionally, knockdown of [[WRN]] reduced [[TNF]]-α stimulation-induced activation of the endogenous promoter of IL-8, an NF-κB-responsive gene, and [[WRN]] increased its association with the IL-8 promoter region together with RelA/p50 after [[TNF]]-α stimulation. In conjunction with studies that have shown NF-κB to be a key regulator of aging and inflammation, our results indicate a novel role of [[WRN]] in transcriptional regulation. Along with NF-κB, the loss of [[WRN]] is expected to result in incorrect regulation of downstream targets and leads to immune abnormalities and homeostatic disruption. 
|mesh-terms=* Aging
* Exodeoxyribonucleases
* HIV-1
* HeLa Cells
* Humans
* Interleukin-8
* NF-kappa B p50 Subunit
* Promoter Regions, Genetic
* RecQ Helicases
* Transcription Factor RelA
* Transcription, Genetic
* Tumor Necrosis Factor-alpha
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* IL-8
* NF-kB transcription factor
* WRN
* Werner syndrome
* aging
* human immunodeficiency virus (HIV)
* retrovirus
* viral transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513100
}}
{{medline-entry
|title=Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25931448
|abstract=Werner syndrome (WS) is a premature aging disorder caused by [[WRN]] protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of [[WRN]]-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that [[WRN]] associates with heterochromatin proteins [[SUV39H1]] and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive [[SUV39H1]] in wild-type MSCs recapitulates accelerated cellular senescence, resembling [[WRN]]-deficient MSCs. Moreover, decrease in [[WRN]] and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for [[WRN]] in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging. 
|mesh-terms=* Aging
* Animals
* Cell Differentiation
* Cellular Senescence
* Centromere
* Chromosomal Proteins, Non-Histone
* DNA-Binding Proteins
* Epigenesis, Genetic
* Exodeoxyribonucleases
* Gene Knockout Techniques
* HEK293 Cells
* Heterochromatin
* Humans
* Membrane Proteins
* Mesenchymal Stem Cells
* Methyltransferases
* Mice
* Models, Biological
* RecQ Helicases
* Repressor Proteins
* Werner Syndrome
* Werner Syndrome Helicase

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494668
}}
{{medline-entry
|title=Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25688260
|abstract=Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by [[WRN]], the gene responsible for WS, has been studied extensively. [[WRN]] helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications. 

|keywords=* Werner syndrome (WS)
* accelerated aging
* chromosomal instability
* induced pluripotent stem cells (iPSCs)
* premature senescence phenotypes
* reprogramming
* telomerase
* telomere dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310323
}}
{{medline-entry
|title=Transient overexpression of Werner protein rescues starvation induced autophagy in Werner syndrome cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25257404
|abstract=Reduced autophagy may be associated with normal and pathological aging. Here we report a link between autophagy and Werner protein ([[WRN]]p), mutated in Werner syndrome, the human premature aging Werner syndrome (WS). [[WRN]] mutant fibroblast AG11395 and AG05229 respond weakly to starvation induced autophagy compared to normal cells. While the fusion of phagosomes with lysosome is normal, WS cells contain fewer autophagy vacuoles. Cellular starvation autophagy in WS cells is restored after transfection with full length [[WRN]]. Further, siRNA mediated silencing of [[WRN]] in the normal fibroblast cell line WI-38 results in decreased autophagy and altered expression of autophagy related proteins. Thus, our observations suggest that [[WRN]] may have a role in controlling autophagy and hereby cellular maintenance. 
|mesh-terms=* Adult
* Autophagy
* Blotting, Western
* Cell Line
* Cells, Cultured
* Culture Media
* Exodeoxyribonucleases
* Fibroblasts
* Gene Expression
* Green Fluorescent Proteins
* Humans
* Male
* Microscopy, Electron, Transmission
* Microscopy, Fluorescence
* Microtubule-Associated Proteins
* Phosphorylation
* RNA Interference
* RecQ Helicases
* TOR Serine-Threonine Kinases
* Transfection
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* Aging
* Autophagy
* Beclin-1
* RecQ helicase
* Werner protein
* Werner syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582615
}}
{{medline-entry
|title=Senescence induced by [[RECQL4]] dysfunction contributes to Rothmund-Thomson syndrome features in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24832598
|abstract=Cellular senescence refers to irreversible growth arrest of primary eukaryotic cells, a process thought to contribute to aging-related degeneration and disease. Deficiency of RecQ helicase [[RECQL4]] leads to Rothmund-Thomson syndrome (RTS), and we have investigated whether senescence is involved using cellular approaches and a mouse model. 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. [[BLM]]-, [[WRN]]- and [[RECQL4]]-depleted cells display increased staining of senescence-associated β-galactosidase (SA-β-gal), higher expression of p16(INK4a) or/and p21(WAF1) and accumulated persistent DNA damage foci. These features were less frequent in RECQL1- and [[RECQL5]]-depleted cells. We have mapped the region in [[RECQL4]] that prevents cellular senescence to its N-terminal region and helicase domain. We further investigated senescence features in an RTS mouse model, Recql4-deficient mice (Recql4(HD)). Tail fibroblasts from Recql4(HD) showed increased SA-β-gal staining and increased DNA damage foci. We also identified sparser tail hair and fewer blood cells in Recql4(HD) mice accompanied with increased senescence in tail hair follicles and in bone marrow cells. In conclusion, dysfunction of [[RECQL4]] increases DNA damage and triggers premature senescence in both human and mouse cells, which may contribute to symptoms in RTS patients. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Bone Marrow Cells
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* Disease Models, Animal
* Exodeoxyribonucleases
* Fibroblasts
* Genetic Predisposition to Disease
* Hair Follicle
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Phenotype
* Protein Structure, Tertiary
* RNA Interference
* RecQ Helicases
* Rothmund-Thomson Syndrome
* Transfection
* Werner Syndrome Helicase

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047874
}}
{{medline-entry
|title=Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24401204
|abstract=Segmental progeroid syndromes are a group of disorders with multiple features resembling accelerated aging. Adult-onset Werner syndrome (WS) and childhood-onset Hutchinson-Gilford progeria syndrome are the best known examples. The discovery of genes responsible for such syndromes has facilitated our understanding of the basic mechanisms of aging as well as the pathogenesis of other common, age-related diseases. Our International Registry of Werner Syndrome accesses progeroid pedigrees from all over the world, including those for whom we have ruled out a mutation at the [[WRN]] locus. Cases without [[WRN]] mutations are operationally categorized as 'atypical WS' (AWS). In 2003, we identified [[LMNA]] mutations among a subset of AWS cases using a candidate gene approach. As of 2013, the Registry has 142 WS patients with [[WRN]] mutations, 11 AWS patients with [[LMNA]] mutations, and 49 AWS patients that have neither [[WRN]] nor [[LMNA]] mutations. Efforts are underway to identify the responsible genes for AWS with unknown genetic causes. While WS and AWS are rare disorders, the causative genes have been shown to have much wider implications for cancer, cardiovascular disease and the biology of aging. Remarkably, centenarian studies revealed [[WRN]] and [[LMNA]] polymorphic variants among those who have escaped various geriatric disorders.
|mesh-terms=* Adult
* Aging
* Aging, Premature
* Child
* Chromosome Aberrations
* Exodeoxyribonucleases
* Female
* Gene Rearrangement
* Humans
* Lamin Type A
* Male
* Mutation
* Progeria
* RecQ Helicases
* Registries
* Werner Syndrome
* Werner Syndrome Helicase

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997596
}}
{{medline-entry
|title=Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23702336
|abstract=Werner syndrome (WS) protein is involved in DNA repair and its truncation causes Werner syndrome, an autosomal recessive genetic disorder with a premature aging phenotype. [[WRN]] protein mutation is currently known as the primary cause of WS. In cultured WS fibroblasts, we found an increase in cytosolic aggregates and hypothesized that the phenotype is indirectly related to an excess activation of the mTOR (mammalian target of rapamycin) pathway, leading to the formation of protein aggregates in the cytosol with increasing levels of oxidative stress. As we found that the expression levels of the two main H2S producing enzymes, cystathionine β synthase and cystathionine γ lyase, were lower in WS cells compared to normal, we investigated the effect of administration of H2S as NaHS (50μM). NaHS treatment blocked mTOR activity, abrogated protein aggregation and normalized the phenotype of WS cells. Similar results were obtained by treatment with the mTOR inhibitor rapamycin. This is the first report suggesting that hydrogen sulfide administered as NaHS restores proteostasis and cellular morphological phenotype of WS cells and hints to the importance of transsulfuration pathway in WS. 
|mesh-terms=* Adolescent
* Adult
* Caspase 3
* Caspase 7
* Cell Line
* Female
* Fibroblasts
* Humans
* Hydrogen Sulfide
* Male
* Middle Aged
* Oxidative Stress
* Phenotype
* Reactive Oxygen Species
* TOR Serine-Threonine Kinases
* Werner Syndrome
* Young Adult
* beta-Galactosidase
|keywords=* Aging
* Autophagy
* NaHS
* Progeria
* Proteostasis
* Werner protein
* mTOR
|full-text-url=https://sci-hub.do/10.1016/j.phrs.2013.04.011
}}
{{medline-entry
|title=Copy number variations of DNA repair genes and the age-related cataract: Jiangsu Eye Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23329665
|abstract=DNA damage is critical in the pathogenesis of age-related cataract ([[ARC]]). This study examined the association of copy number variations (CNVs) of DNA repair genes with susceptibility to [[ARC]] in the Han Chinese. Study participants were from the population-based Jiangsu Eye Study, which includes 780 [[ARC]] patients and 525 controls. DNA was extracted from blood for copy number (CN) assays using RT-PCR. The Comet assay was to assess DNA damage in peripheral lymphocytes. Novel CNV was detected in [[WRN]]. Initial analyses found that CN = 3  for [[WRN]] had an increased risk of [[ARC]] (odds ratio [OR] = 1.88, P = 0.02); CN = 1 for [[HSF4]] had an increased risk of [[ARC]] (OR = 4.09, P = 0.004). CN = 3  for [[WRN]] was associated with nuclear and posterior subcapsular cataract (OR = 2.06, P = 0.02; OR = 3.72, P = 0.02). CN = 1 for [[HSF4]] was associated with nuclear and posterior subcapsular cataract (OR = 5.73, P = 0.001; OR = 6.80, P = 0.01). The combination [[WRN]] and [[HSF4]] CNVs markedly increased the risk of [[ARC]]; the OR was increased from 2.63 by [[HSF4]] alone to 6.80 by combined [[WRN]] and [[HSF4]] CNVs. However, after multiple testing correction, only [[HSF4]] CNV was associated with [[ARC]] overall and with nuclear and posterior subcapsular cataract as well. The DNA damage in lymphocytes from [[ARC]] patients was significantly higher when compared to normal controls. [[HSF4]] and [[WRN]] CNVs might be involved in [[ARC]] pathogenesis in the Han Chinese. These findings suggest the importance of DNA repair in [[ARC]] susceptibility and distinct risk factors in [[ARC]] subtypes.
|mesh-terms=* Aged
* Aging
* Asian Continental Ancestry Group
* Cataract
* China
* Comet Assay
* DNA
* DNA Copy Number Variations
* DNA-Binding Proteins
* Exodeoxyribonucleases
* Female
* Genetic Predisposition to Disease
* Genotype
* Heat Shock Transcription Factors
* Humans
* Male
* Odds Ratio
* RecQ Helicases
* Reverse Transcriptase Polymerase Chain Reaction
* Transcription Factors
* Werner Syndrome Helicase

|full-text-url=https://sci-hub.do/10.1167/iovs.12-10948
}}
{{medline-entry
|title=The associations between single nucleotide polymorphisms of DNA repair genes, DNA damage, and age-related cataract: Jiangsu Eye Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23322570
|abstract=Age-related cataract ([[ARC]]) is one of the most common causes of severe visual impairment among the elderly worldwide with four subtypes, such as cortical, nuclear, subcapsular, and mixed types. DNA damage and malfunction of DNA repair are believed to contribute to the pathogenesis of [[ARC]]. This study examined the associations of 18 single nucleotide polymorphisms (SNPs) in four DNA repair genes ([[BLM]], [[WRN]], [[[[ERCC6]]]], and OGG1) with [[ARC]] in Han Chinese from the Jiangsu Eye Study, a population-based epidemiologic study. We also determined the possible functional consequence of the SNPs to DNA damage. Eighteen SNPs in four DNA repair genes were genotyped in 789 [[ARC]] patients and 531 normal controls from the Jiangsu Eye Study. The Comet assay was to assess the extent of DNA damage in peripheral lymphocytes of selected subjects. The results show that [[WRN]]-rs11574311 was initially associated with [[ARC]] in general, cortical, and mixed cataracts (P = 0.003, odds ratio [OR] = 1.49; P = 0.001, OR = 1.68; and P < 0.0001, OR = 2.08), [[BLM]]-rs1063147 with nuclear cataract (P = 0.03, OR = 1.31), [[WRN]]-rs2725383 with cortical cataract (P = 0.01, OR = 1.49), and [[WRN]]-rs4733220 and [[WRN]]-rs2725338 with mixed cataract (P = 0.04, OR = 0.74; P = 0.003, OR = 0.60). However, the significances of some of the above-cited associations disappeared after multiple testing corrections. [[WRN]]-rs11574311 remains associated with cortical and mixed cataract and [[WRN]]-rs2725338 with mixed cataract after multiple testing correction. We did not find any correlation between DNA damage of peripheral lymphocytes and SNP types. We concluded that [[WRN]] genes might be involved in [[ARC]] pathogenesis in the Han Chinese population. The associations were [[ARC]] subtype specific. These findings stress the importance of detailed phenotyping in [[ARC]] subtypes, which may be associated with different risk factors and disease mechanisms.
|mesh-terms=* Adult
* Aged
* Aging
* Asian Continental Ancestry Group
* Cataract
* China
* Comet Assay
* DNA Damage
* DNA Glycosylases
* DNA Helicases
* DNA Repair
* DNA Repair Enzymes
* Exodeoxyribonucleases
* Female
* Genetic Predisposition to Disease
* Haplotypes
* Humans
* Lymphocytes
* Male
* Middle Aged
* Poly-ADP-Ribose Binding Proteins
* Polymorphism, Single Nucleotide
* RecQ Helicases
* Risk Factors
* Werner Syndrome Helicase

|full-text-url=https://sci-hub.do/10.1167/iovs.12-10940
}}
{{medline-entry
|title=Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23257959
|abstract=DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the [[LMNA]] and [[WRN]] genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of [[WRN]] and [[LMNA]] mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.
|mesh-terms=* Aging, Premature
* Case-Control Studies
* Cell Line, Transformed
* DNA Methylation
* Female
* Genetic Association Studies
* Humans
* Male
* Mutation
* Phenotype
* Progeria
* Werner Syndrome
|keywords=* DNA methylation
* DNA methylation BeadChip
* HGP
* Hutchinson-Gilford Progeria Syndrome
* LMNA
* LOC149837
* MYB
* WRN
* Werner Syndrome
* premature aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549877
}}