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[PMID]:28654322
[Au] Autor:Fresco JR; Amosova O
[Ad] Endereço:Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544; email: jrfresco@princeton.edu , amosova@princeton.edu.
[Ti] Título:Site-Specific Self-Catalyzed DNA Depurination: A Biological Mechanism That Leads to Mutations and Creates Sequence Diversity.
[So] Source:Annu Rev Biochem;86:461-484, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Self-catalyzed DNA depurination is a sequence-specific physiological mechanism mediated by spontaneous extrusion of a stem-loop catalytic intermediate. Hydrolysis of the 5'G residue of the 5'GA/TGG loop and of the first 5'A residue of the 5'GAGA loop, together with particular first stem base pairs, specifies their hydrolysis without involving protein, cofactor, or cation. As such, this mechanism is the only known DNA catalytic activity exploited by nature. The consensus sequences for self-depurination of such G- and A-loop residues occur in all genomes examined across the phyla, averaging one site every 2,000-4,000 base pairs. Because apurinic sites are subject to error-prone repair, leading to substitution and short frameshift mutations, they are both a source of genome damage and a means for creating sequence diversity. Their marked overrepresentation in genomes, and largely unchanging density from the lowest to the highest organisms, indicate their selection over the course of evolution. The mutagenicity at such sites in many human genes is associated with loss of function of key proteins responsible for diverse diseases.
[Mh] Termos MeSH primário: Adenina/metabolismo
Síndrome de Bloom/genética
DNA Catalítico/genética
Guanina/metabolismo
Polimorfismo Genético
Síndrome de Werner/genética
[Mh] Termos MeSH secundário: Evolução Biológica
Síndrome de Bloom/metabolismo
Síndrome de Bloom/patologia
Catálise
Reparo do DNA
DNA Catalítico/metabolismo
DNA Cruciforme/genética
DNA Cruciforme/metabolismo
DNA de Cadeia Simples/genética
DNA de Cadeia Simples/metabolismo
Seres Humanos
Hidrólise
Sequências Repetidas Invertidas
Mutação
Síndrome de Werner/metabolismo
Síndrome de Werner/patologia
Globinas beta/genética
Globinas beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA, Catalytic); 0 (DNA, Cruciform); 0 (DNA, Single-Stranded); 0 (beta-Globins); 5Z93L87A1R (Guanine); JAC85A2161 (Adenine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-070611-095951


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[PMID]:28538897
[Au] Autor:Bilgiç Ö
[Ad] Endereço:School of Medicine, Selcuk University - Konya, Turkey.
[Ti] Título:Do you know this syndrome? Werner syndrome.
[So] Source:An Bras Dermatol;92(2):271-272, 2017 Mar-Apr.
[Is] ISSN:1806-4841
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Werner syndrome is a rare autosomal recessive disorder, caused by mutations in the WRN gene. Clinical findings include: senile appearance, short stature, grey hair, alopecia, bird-like face, scleroderma-like skin changes, skin ulcers, voice abnormalities, cataracts, osteoporosis, type 2 diabetes mellitus, ischemic heart disease and hypogonadism. The syndrome begins to become apparent in adolescence but it is usually diagnosed in the third or fourth decade of life. Since the patients usually die by the age of 40-50 years related to malignant neoplasms or atherosclerotic complications, they should be closely followed and treated for complications.
[Mh] Termos MeSH primário: Síndrome de Werner/diagnóstico
[Mh] Termos MeSH secundário: Adulto
Diagnóstico Diferencial
Seres Humanos
Úlcera da Perna/etiologia
Masculino
Esclerodermia Localizada
Síndrome de Werner/complicações
[Pt] Tipo de publicação:CASE REPORTS
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE


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[PMID]:28394436
[Au] Autor:Yamaga M; Takemoto M; Takada-Watanabe A; Koizumi N; Kitamoto T; Sakamoto K; Ishikawa T; Koshizaka M; Maezawa Y; Yokote K
[Ad] Endereço:Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
[Ti] Título:Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.
[So] Source:J Am Geriatr Soc;65(8):1853-1856, 2017 Aug.
[Is] ISSN:1532-5415
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. DESIGN: Retrospective cohort. SETTING: Longitudinal survey of WS and literature search for case reports. PARTICIPANTS: Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). MEASUREMENTS: A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. RESULTS: A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. CONCLUSION: The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future.
[Mh] Termos MeSH primário: Mutação/genética
Helicase da Síndrome de Werner/genética
Síndrome de Werner/epidemiologia
[Mh] Termos MeSH secundário: Heterozigoto
Seres Humanos
Japão
Estudos Retrospectivos
Síndrome de Werner/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.6.4.12 (WRN protein, human); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1111/jgs.14906


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[PMID]:28069813
[Au] Autor:Ketkar A; Voehler M; Mukiza T; Eoff RL
[Ad] Endereço:From the Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199 and.
[Ti] Título:Residues in the RecQ C-terminal Domain of the Human Werner Syndrome Helicase Are Involved in Unwinding G-quadruplex DNA.
[So] Source:J Biol Chem;292(8):3154-3163, 2017 Feb 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The structural and biophysical properties typically associated with G-quadruplex (G4) structures render them a significant block for DNA replication, which must be overcome for cell division to occur. The Werner syndrome protein (WRN) is a RecQ family helicase that has been implicated in the efficient processing of G4 DNA structures. The aim of this study was to identify the residues of WRN involved in the binding and ATPase-driven unwinding of G4 DNA. Using a c-Myc G4 DNA model sequence and recombinant WRN, we have determined that the RecQ-C-terminal (RQC) domain of WRN imparts a 2-fold preference for binding to G4 DNA relative to non-G4 DNA substrates. NMR studies identified residues involved specifically in interactions with G4 DNA. Three of the amino acids in the WRN RQC domain that exhibited the largest G4-specific changes in NMR signal were then mutated alone or in combination. Mutating individual residues implicated in G4 binding had a modest effect on WRN binding to DNA, decreasing the preference for G4 substrates by ∼25%. Mutating two G4-interacting residues (T1024G and T1086G) abrogated preferential binding of WRN to G4 DNA. Very modest decreases in G4 DNA-stimulated ATPase activity were observed for the mutant enzymes. Most strikingly, G4 unwinding by WRN was inhibited ∼50% for all three point mutants and >90% for the WRN double mutant (T1024G/T1086G) relative to normal B-form dsDNA substrates. Our work has helped to identify residues in the WRN RQC domain that are involved specifically in the interaction with G4 DNA.
[Mh] Termos MeSH primário: DNA/metabolismo
Quadruplex G
Helicase da Síndrome de Werner/metabolismo
Síndrome de Werner/enzimologia
[Mh] Termos MeSH secundário: DNA/química
DNA/genética
Reparo do DNA
Replicação do DNA
Seres Humanos
Modelos Moleculares
Mutação
Domínios Proteicos
Síndrome de Werner/genética
Síndrome de Werner/metabolismo
Helicase da Síndrome de Werner/química
Helicase da Síndrome de Werner/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.767699


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[PMID]:27238185
[Au] Autor:de Renty C; Ellis NA
[Ad] Endereço:University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ 81724, United States.
[Ti] Título:Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases.
[So] Source:Ageing Res Rev;33:36-51, 2017 Jan.
[Is] ISSN:1872-9649
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Senilidade Prematura/genética
Envelhecimento/genética
DNA Helicases/fisiologia
RecQ Helicases/genética
Helicase da Síndrome de Werner/genética
[Mh] Termos MeSH secundário: Síndrome de Bloom/diagnóstico
Síndrome de Bloom/genética
Replicação do DNA
Instabilidade Genômica
Seres Humanos
Mutação
Síndrome de Werner/diagnóstico
Síndrome de Werner/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.6.1.- (Bloom syndrome protein); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (RecQ Helicases); EC 3.6.4.12 (WRN protein, human); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160531
[St] Status:MEDLINE


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[PMID]:26993153
[Au] Autor:Oshima J; Sidorova JM; Monnat RJ
[Ad] Endereço:Department of Pathology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Chiba University, Chiba, Japan. Electronic address: picard@u.washington.edu.
[Ti] Título:Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions.
[So] Source:Ageing Res Rev;33:105-114, 2017 Jan.
[Is] ISSN:1872-9649
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Werner syndrome (WS) is a prototypical segmental progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related progeroid syndromes.
[Mh] Termos MeSH primário: Senilidade Prematura
Helicase da Síndrome de Werner/genética
Síndrome de Werner
[Mh] Termos MeSH secundário: Senilidade Prematura/genética
Senilidade Prematura/metabolismo
Reparo do DNA
Replicação do DNA
Exodesoxirribonucleases
Seres Humanos
Mutação
Síndrome de Werner/diagnóstico
Síndrome de Werner/genética
Síndrome de Werner/metabolismo
Síndrome de Werner/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.1.- (Exodeoxyribonucleases); EC 3.6.4.12 (WRN protein, human); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160320
[St] Status:MEDLINE


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[PMID]:27808039
[Au] Autor:Scheibye-Knudsen M
[Ad] Endereço:mscheibye@sund.ku.dk.
[Ti] Título:Neurodegeneration in accelerated aging.
[So] Source:Dan Med J;63(11), 2016 Nov.
[Is] ISSN:2245-1919
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic strategy for treating accelerated aging disorders and potentially age-associated neurological decline seen in the normal population.
[Mh] Termos MeSH primário: Senilidade Prematura/genética
Senilidade Prematura/metabolismo
Síndrome de Cockayne/fisiopatologia
Reparo do DNA/genética
Mitocôndrias/fisiologia
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/metabolismo
[Mh] Termos MeSH secundário: Animais
Ataxia Telangiectasia/genética
Síndrome de Bloom/genética
Síndrome de Cockayne/genética
Reparo do DNA/fisiologia
Disceratose Congênita/genética
Anemia de Fanconi/genética
Seres Humanos
Degradação Mitocondrial
NAD/metabolismo
Poli(ADP-Ribose) Polimerases/metabolismo
Progéria/genética
Progéria/metabolismo
Síndrome de Rothmund-Thomson/genética
Sirtuína 1/metabolismo
Encurtamento do Telômero
Síndrome de Werner/enzimologia
Síndrome de Werner/genética
Xeroderma Pigmentoso/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0U46U6E8UK (NAD); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 3.5.1.- (SIRT1 protein, human); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170314
[Lr] Data última revisão:
170314
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161104
[St] Status:MEDLINE


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[PMID]:27492502
[Au] Autor:Ibrahim B; Sheerin AN; Jennert-Burston K; Bird JL; Massala MV; Illsley M; James SE; Faragher RG
[Ad] Endereço:School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: badr_ibrahim@ymail.com.
[Ti] Título:Absence of premature senescence in Werner's syndrome keratinocytes.
[So] Source:Exp Gerontol;83:139-47, 2016 Oct.
[Is] ISSN:1873-6815
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve <20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome.
[Mh] Termos MeSH primário: Senescência Celular
Queratinócitos/citologia
Helicase da Síndrome de Werner/genética
Síndrome de Werner/genética
[Mh] Termos MeSH secundário: Biomarcadores/análise
Células Cultivadas
Replicação do DNA
Fibroblastos/metabolismo
Seres Humanos
Fenótipo
Telomerase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); EC 2.7.7.49 (Telomerase); EC 3.6.4.12 (WRN protein, human); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160806
[St] Status:MEDLINE


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[PMID]:27320729
[Au] Autor:Nicolas E; Golemis EA; Arora S
[Ad] Endereço:Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
[Ti] Título:POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies.
[So] Source:Gene;590(1):128-41, 2016 Sep 15.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The evolutionarily conserved human polymerase delta (POLD1) gene encodes the large p125 subunit which provides the essential catalytic activities of polymerase δ (Polδ), mediated by 5'-3' DNA polymerase and 3'-5' exonuclease moieties. POLD1 associates with three smaller subunits (POLD2, POLD3, POLD4), which together with Replication Factor C and Proliferating Nuclear Cell Antigen constitute the polymerase holoenzyme. Polδ function is essential for replication, with a primary role as the replicase for the lagging strand. Polδ also has an important proofreading ability conferred by the exonuclease activity, which is critical for ensuring replicative fidelity, but also serves to repair DNA lesions arising as a result of exposure to mutagens. Polδ has been shown to be important for multiple forms of DNA repair, including nucleotide excision repair, double strand break repair, base excision repair, and mismatch repair. A growing number of studies in the past decade have linked germline and sporadic mutations in POLD1 and the other subunits of Polδ with human pathologies. Mutations in Polδ in mice and humans lead to genomic instability, mutator phenotype and tumorigenesis. The advent of genome sequencing techniques has identified damaging mutations in the proofreading domain of POLD1 as the underlying cause of some inherited cancers, and suggested that mutations in POLD1 may influence therapeutic management. In addition, mutations in POLD1 have been identified in the developmental disorders of mandibular hypoplasia, deafness, progeroid features and lipodystrophy and atypical Werner syndrome, while changes in expression or activity of POLD1 have been linked to senescence and aging. Intriguingly, some recent evidence suggests that POLD1 function may also be altered in diabetes. We provide an overview of critical Polδ activities in the context of these pathologic conditions.
[Mh] Termos MeSH primário: Envelhecimento/genética
DNA Polimerase III/genética
Reparo do DNA
Replicação do DNA
Neoplasias/genética
Subunidades Proteicas/genética
[Mh] Termos MeSH secundário: Envelhecimento/metabolismo
Envelhecimento/patologia
Animais
Carcinogênese/genética
Carcinogênese/metabolismo
Carcinogênese/patologia
DNA Polimerase III/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Camundongos
Mutação
Neoplasias/metabolismo
Neoplasias/patologia
Antígeno Nuclear de Célula em Proliferação/genética
Antígeno Nuclear de Célula em Proliferação/metabolismo
Subunidades Proteicas/metabolismo
Proteína de Replicação C/genética
Proteína de Replicação C/metabolismo
Transdução de Sinais
Síndrome de Werner/genética
Síndrome de Werner/metabolismo
Síndrome de Werner/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Proliferating Cell Nuclear Antigen); 0 (Protein Subunits); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (POLD1 protein, human); EC 3.6.4.- (Replication Protein C)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160621
[St] Status:MEDLINE


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[PMID]:27271327
[Au] Autor:Li Y; Zhang W; Chang L; Han Y; Sun L; Gong X; Tang H; Liu Z; Deng H; Ye Y; Wang Y; Li J; Qiao J; Qu J; Zhang W; Liu GH
[Ad] Endereço:National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
[Ti] Título:Vitamin C alleviates aging defects in a stem cell model for Werner syndrome.
[So] Source:Protein Cell;7(7):478-88, 2016 Jul.
[Is] ISSN:1674-8018
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: Ácido Ascórbico/farmacologia
Senescência Celular/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
Síndrome de Werner/metabolismo
[Mh] Termos MeSH secundário: Animais
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Dano ao DNA
Reparo do DNA/efeitos dos fármacos
Replicação do DNA/efeitos dos fármacos
Modelos Animais de Doenças
Heterocromatina/metabolismo
Heterocromatina/patologia
Seres Humanos
Células Mesenquimais Estromais/patologia
Camundongos
Lâmina Nuclear/metabolismo
Lâmina Nuclear/patologia
Espécies Reativas de Oxigênio/metabolismo
Homeostase do Telômero/efeitos dos fármacos
Síndrome de Werner/tratamento farmacológico
Síndrome de Werner/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterochromatin); 0 (Reactive Oxygen Species); PQ6CK8PD0R (Ascorbic Acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.1007/s13238-016-0278-1



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