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  1 / 2958 MEDLINE  
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[PMID]:27771441
[Au] Autor:Wang J; Liu H; Ma C; Wang J; Zhong L; Wu K
[Ad] Endereço:State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, China.
[Ti] Título:Label-free monitoring of DNA polymerase activity based on a thrombin-binding aptamer G-quadruplex.
[So] Source:Mol Cell Probes;32:13-17, 2017 04.
[Is] ISSN:1096-1194
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We have developed a label-free assay for the detection of DNA polymerase activity based on a thrombin-binding aptamer (TBA) G-quadruplex. In the presence of DNA polymerase, the 3'-OH termini of the hairpin substrate are immediately elongated to replace the TBA, which can be recognized quickly by the ThT dye and results in an increase of fluorescence. This method is highly sensitive with a detection limit of 0.1 U/mL. It is simple and cost-effective without any requirement of labeling with a fluorophore-quencher pair. Furthermore, the proposed method can also be applied to analyze the inhibition of DNA polymerase, which clearly indicates that the proposed method can be applied for screening of potential DNA polymerase inhibitors.
[Mh] Termos MeSH primário: Aptâmeros de Nucleotídeos/metabolismo
DNA Polimerase Dirigida por DNA/metabolismo
Quadruplex G
Coloração e Rotulagem
[Mh] Termos MeSH secundário: Sequência de Bases
DNA Polimerase I/metabolismo
Sondas de DNA/metabolismo
Fluorescência
Tiazóis/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aptamers, Nucleotide); 0 (DNA Probes); 0 (Thiazoles); 145563-68-4 (thrombin aptamer); 2390-54-7 (thioflavin T); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  2 / 2958 MEDLINE  
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[PMID]:28934494
[Au] Autor:Oscorbin IP; Belousova EA; Boyarskikh UA; Zakabunin AI; Khrapov EA; Filipenko ML
[Ad] Endereço:Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Avenue 8, Novosibirsk 630090, Russian Federation.
[Ti] Título:Derivatives of Bst-like Gss-polymerase with improved processivity and inhibitor tolerance.
[So] Source:Nucleic Acids Res;45(16):9595-9610, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:At the moment, one of the actual trends in medical diagnostics is a development of methods for practical applications such as point-of-care testing, POCT or research tools, for example, whole genome amplification, WGA. All the techniques are based on using of specific DNA polymerases having strand displacement activity, high synthetic processivity, fidelity and, most significantly, tolerance to contaminants, appearing from analysed biological samples or collected under purification procedures. Here, we have designed a set of fusion enzymes based on catalytic domain of DNA polymerase I from Geobacillus sp. 777 with DNA-binding domain of DNA ligase Pyrococcus abyssi and Sto7d protein from Sulfolobus tokodaii, analogue of Sso7d. Designed chimeric DNA polymerases DBD-Gss, Sto-Gss and Gss-Sto exhibited the same level of thermal stability, thermal transferase activity and fidelity as native Gss; however, the processivity was increased up to 3-fold, leading to about 4-fold of DNA product in WGA which is much more exiting. The attachment of DNA-binding proteins enhanced the inhibitor tolerance of chimeric polymerases in loop-mediated isothermal amplification to several of the most common DNA sample contaminants-urea and whole blood, heparin, ethylenediaminetetraacetic acid, NaCl, ethanol. Therefore, chimeric Bst-like Gss-polymerase will be promising tool for both WGA and POCT due to increased processivity and inhibitor tolerance.
[Mh] Termos MeSH primário: DNA Polimerase I/metabolismo
Geobacillus/enzimologia
Engenharia de Proteínas/métodos
Proteínas Recombinantes de Fusão/genética
[Mh] Termos MeSH secundário: Domínio Catalítico
Clonagem Molecular
DNA/metabolismo
DNA Polimerase I/antagonistas & inibidores
DNA Polimerase I/genética
Inibidores Enzimáticos/farmacologia
Genoma Humano
Geobacillus/genética
Geobacillus stearothermophilus/enzimologia
Geobacillus stearothermophilus/genética
Seres Humanos
Técnicas de Amplificação de Ácido Nucleico/métodos
Estabilidade Proteica
Pyrococcus abyssi/genética
Proteínas Recombinantes de Fusão/metabolismo
Sulfolobus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Recombinant Fusion Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx645


  3 / 2958 MEDLINE  
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[PMID]:28934486
[Au] Autor:Ganduri S; Lue NF
[Ad] Endereço:Department of Microbiology & Immunology, W. R. Hearst Microbiology Research Center, Weill Cornell Medical College, New York, NY 10065, USA.
[Ti] Título:STN1-POLA2 interaction provides a basis for primase-pol α stimulation by human STN1.
[So] Source:Nucleic Acids Res;45(16):9455-9466, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The CST (CTC1-STN1-TEN1) complex mediates critical functions in maintaining telomere DNA and overcoming genome-wide replication stress. A conserved biochemical function of the CST complex is its primase-Pol α (PP) stimulatory activity. In this report, we demonstrate the ability of purified human STN1 alone to promote PP activity in vitro. We show that this regulation is mediated primarily by the N-terminal OB fold of STN1, but does not require the DNA-binding activity of this domain. Rather, we observed a strong correlation between the PP-stimulatory activity of STN1 variants and their abilities to bind POLA2. Remarkably, the main binding target of STN1 in POLA2 is the latter's central OB fold domain. In the substrate-free structure of PP, this domain is positioned so as to block nucleic acid entry to the Pol α active site. Thus the STN1-POLA2 interaction may promote the necessary conformational change for nucleic acid delivery to Pol α and subsequent DNA synthesis. A disease-causing mutation in human STN1 engenders a selective defect in POLA2-binding and PP stimulation, indicating that these activities are critical for the in vivo function of STN1. Our findings have implications for the molecular mechanisms of PP, STN1 and STN1-related molecular pathology.
[Mh] Termos MeSH primário: DNA Polimerase I/metabolismo
DNA Primase/metabolismo
Proteínas de Ligação a Telômeros/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
DNA/metabolismo
DNA Polimerase I/química
DNA Polimerase I/genética
DNA Primase/química
DNA Primase/genética
Seres Humanos
Mutação Puntual
Domínios Proteicos
Subunidades Proteicas
Proteínas de Ligação a Telômeros/química
Proteínas de Ligação a Telômeros/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Subunits); 0 (Stn1 protein, human); 0 (Telomere-Binding Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.- (DNA Primase); EC 2.7.7.- (DNA polymerase alpha-primase); EC 2.7.7.- (POLA2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx621


  4 / 2958 MEDLINE  
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[PMID]:28807995
[Au] Autor:Matsuda S; Hammaker D; Topolewski K; Briegel KJ; Boyle DL; Dowdy S; Wang W; Firestein GS
[Ad] Endereço:Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, La Jolla, CA 92093.
[Ti] Título:Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor Gene.
[So] Source:J Immunol;199(7):2316-2322, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development ( ) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. knockout exacerbated disease severity, which is associated with elevated levels of IL-1ß and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.
[Mh] Termos MeSH primário: Artrite Reumatoide/genética
Ciclo Celular/genética
Proteínas Nucleares/genética
Sinoviócitos/imunologia
[Mh] Termos MeSH secundário: Animais
Artrite Experimental
Artrite Reumatoide/imunologia
Artrite Reumatoide/fisiopatologia
Células Cultivadas
Quinase do Ponto de Checagem 1/genética
Dano ao DNA
DNA Polimerase I/genética
DNA Polimerase I/metabolismo
Regulação da Expressão Gênica
Genes cdc
Seres Humanos
Interleucina-1beta/biossíntese
Camundongos
Camundongos Knockout
Proteínas Nucleares/deficiência
Proteínas Nucleares/metabolismo
Fosforilação
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-1beta); 0 (Lbh protein, mouse); 0 (Nuclear Proteins); EC 2.7.11.1 (Checkpoint Kinase 1); EC 2.7.11.1 (Chek1 protein, mouse); EC 2.7.7.- (DNA Polymerase I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700719


  5 / 2958 MEDLINE  
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[PMID]:28757209
[Au] Autor:Kolinjivadi AM; Sannino V; De Antoni A; Zadorozhny K; Kilkenny M; Técher H; Baldi G; Shen R; Ciccia A; Pellegrini L; Krejci L; Costanzo V
[Ad] Endereço:DNA Metabolism Laboratory, IFOM, FIRC Institute for Molecular Oncology, 20139 Milan, Italy.
[Ti] Título:Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments.
[So] Source:Mol Cell;67(5):867-881.e7, 2017 Sep 07.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brca2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis Brca2. We demonstrated that Brca2 protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without Brca2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51 mutant proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of Brca2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that Brca2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.
[Mh] Termos MeSH primário: Proteína BRCA2/metabolismo
Replicação do DNA
DNA/biossíntese
Rad51 Recombinase/metabolismo
Proteínas de Xenopus/metabolismo
Xenopus laevis/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína BRCA2/genética
Sítios de Ligação
DNA/genética
DNA Helicases/genética
DNA Helicases/metabolismo
DNA Polimerase I/metabolismo
DNA Polimerase III/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Endodesoxirribonucleases/genética
Endodesoxirribonucleases/metabolismo
Exodesoxirribonucleases/genética
Exodesoxirribonucleases/metabolismo
Feminino
Instabilidade Genômica
Seres Humanos
Proteína Homóloga a MRE11
Masculino
Mutação
Ligação Proteica
Rad51 Recombinase/genética
Origem de Replicação
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Fatores de Tempo
Proteínas de Xenopus/genética
Xenopus laevis/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA2 Protein); 0 (DNA-Binding Proteins); 0 (MRE11A protein, human); 0 (Saccharomyces cerevisiae Proteins); 0 (Xenopus Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (RAD51 protein, Xenopus); EC 2.7.7.- (RAD51 protein, human); EC 2.7.7.- (Rad51 Recombinase); EC 2.7.7.- (SMARCAL1 protein, human); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (MRE11 Homologue Protein); EC 3.1.- (MRE11 protein, S cerevisiae); EC 3.6.4.- (DNA Helicases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


  6 / 2958 MEDLINE  
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[PMID]:28510759
[Au] Autor:Perez-Arnaiz P; Bruck I; Colbert MK; Kaplan DL
[Ad] Endereço:Florida State University College of Medicine, Department of Biomedical Sciences, Tallahassee, FL 32306, USA.
[Ti] Título:An intact Mcm10 coiled-coil interaction surface is important for origin melting, helicase assembly and the recruitment of Pol-α to Mcm2-7.
[So] Source:Nucleic Acids Res;45(12):7261-7275, 2017 Jul 07.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mcm10 is an essential eukaryotic factor required for DNA replication. The replication fork helicase is composed of Cdc45, Mcm2-7 and GINS (CMG). DDK is an S-phase-specific kinase required for replication initiation, and the DNA primase-polymerase in eukaryotes is pol α. Mcm10 forms oligomers in vitro, mediated by the coiled-coil domain at the N-terminal region of the protein. We characterized an Mcm10 mutant at the N-terminal Domain (NTD), Mcm10-4A, defective for self-interaction. We found that the Mcm10-4A mutant was defective for stimulating DDK phosphorylation of Mcm2, binding to eighty-nucleotide ssDNA, and recruiting pol α to Mcm2-7 in vitro. Expression of wild-type levels of mcm10-4A resulted in severe growth and DNA replication defects in budding yeast cells, with diminished DDK phosphorylation of Mcm2. We then expressed the mcm10-4A in mcm5-bob1 mutant cells to bypass the defects mediated by diminished stimulation of DDK phosphorylation of Mcm2. Expression of wild-type levels of mcm10-4A in mcm5-bob1 mutant cells resulted in severe growth and DNA replication defects, along with diminished RPA signal at replication origins. We also detected diminished GINS and pol-α recruitment to the Mcm2-7 complex. We conclude that an intact Mcm10 coiled-coil interaction surface is important for origin melting, helicase assembly, and the recruitment of pol α to Mcm2-7.
[Mh] Termos MeSH primário: DNA Polimerase I/genética
Replicação do DNA
Proteínas de Manutenção de Minicromossomo/genética
Proteínas de Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/genética
[Mh] Termos MeSH secundário: Animais
Proteínas de Ciclo Celular/genética
Proteínas de Ciclo Celular/metabolismo
DNA Polimerase I/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Seres Humanos
Cinética
Camundongos
Proteínas de Manutenção de Minicromossomo/metabolismo
Mutação
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Fosforilação
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Xenopus laevis/genética
Xenopus laevis/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDC45 protein, S cerevisiae); 0 (Cell Cycle Proteins); 0 (DNA-Binding Proteins); 0 (MCM10 protein, S cerevisiae); 0 (MCM5 protein, S cerevisiae); 0 (Nuclear Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.- (CDC7 protein, S cerevisiae); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.7.- (DNA Polymerase I); EC 3.6.4.12 (Minichromosome Maintenance Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx438


  7 / 2958 MEDLINE  
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[PMID]:28402640
[Au] Autor:Gowda ASP; Krzeminski J; Amin S; Suo Z; Spratt TE
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine , Hershey, Pennsylvania 17033, United States.
[Ti] Título:Mutagenic Replication of N -Deoxyguanosine Benzo[a]pyrene Adducts by Escherichia coli DNA Polymerase I and Sulfolobus solfataricus DNA Polymerase IV.
[So] Source:Chem Res Toxicol;30(5):1168-1176, 2017 May 15.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Benzo[a]pyrene, a potent human carcinogen, is metabolized in vivo to a diol epoxide that reacts with the N -position of guanine to produce N -BP-dG adducts. These adducts are mutagenic causing G to T transversions. These adducts block replicative polymerases but can be bypassed by the Y-family translesion synthesis polymerases. The mechanisms by which mutagenic bypass occurs is not well-known. We have evaluated base pairing structures using atomic substitution of the dNTP with two stereoisomers, 2'-deoxy-N-[(7R,8S,9R,10S)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine and 2'-deoxy-N-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine. We have examined the kinetics of incorporation of 1-deaza-dATP, 7-deaza-dATP, 2'-deoxyinosine triphosphate, and 7-deaza-dGTP, analogues of dATP and dGTP in which single atoms are changed. Changes in rate will occur if that atom provided a critical interaction in the transition state of the reaction. We examined two polymerases, Escherichia coli DNA polymerase I (Kf) and Sulfolobus solfataricus DNA polymerase IV (Dpo4), as models of a high fidelity and TLS polymerase, respectively. We found that with Kf, substitution of the nitrogens on the Watson-Crick face of the dNTPs resulted in decreased rate of reactions. This result is consistent with a Hoogsteen base pair in which the template N -BP-dG flipped from the anti to syn conformation. With Dpo4, while the substitution did not affect the rate of reaction, the amplitude of the reaction decreased with all substitutions. This result suggests that Dpo4 bypasses N -BP-dG via Hoogsteen base pairs but that the flipped nucleotide can be either the dNTP or the template.
[Mh] Termos MeSH primário: Benzopirenos/metabolismo
Adutos de DNA
DNA Polimerase I/metabolismo
DNA Polimerase beta/metabolismo
Replicação do DNA
Desoxiguanosina/análogos & derivados
Escherichia coli/enzimologia
Sulfolobus solfataricus/enzimologia
[Mh] Termos MeSH secundário: Pareamento de Bases
Catálise
Desoxiguanosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzopyrenes); 0 (DNA Adducts); 0 (benzo(a)pyrene N2-dG adduct); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.- (DNA Polymerase beta); G9481N71RO (Deoxyguanosine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.6b00466


  8 / 2958 MEDLINE  
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[PMID]:28381552
[Au] Autor:Guan C; Li J; Sun D; Liu Y; Liang H
[Ad] Endereço:From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 and.
[Ti] Título:The structure and polymerase-recognition mechanism of the crucial adaptor protein AND-1 in the human replisome.
[So] Source:J Biol Chem;292(23):9627-9636, 2017 Jun 09.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA replication in eukaryotic cells is performed by a multiprotein complex called the replisome, which consists of helicases, polymerases, and adaptor molecules. Human cidic ucleoplasmic NA-binding protein 1 (AND-1), also known as WD repeat and high mobility group (HMG)-box DNA-binding protein 1 (WDHD1), is an adaptor molecule crucial for DNA replication. Although structural information for the AND-1 yeast ortholog is available, the mechanistic details for how human AND-1 protein anchors the lagging-strand DNA polymerase α (pol α) to the DNA helicase complex ( dc45- CM2-7- INS, CMG) await elucidation. Here, we report the structures of the N-terminal WD40 and SepB domains of human AND-1, as well as a biochemical analysis of the C-terminal HMG domain. We show that AND-1 exists as a homotrimer mediated by the SepB domain. Mutant study results suggested that a positively charged groove within the SepB domain provides binding sites for pol α. Different from its ortholog protein in budding yeast, human AND-1 is recruited to the CMG complex, mediated by unknown participants other than Go Ichi Ni San. In addition, we show that AND-1 binds to DNA , using its C-terminal HMG domain. In conclusion, our findings provide important insights into the mechanistic details of human AND-1 function, advancing our understanding of replisome formation during eukaryotic replication.
[Mh] Termos MeSH primário: DNA Helicases/química
DNA Polimerase I/química
Proteínas de Ligação a DNA/química
DNA/química
Complexos Multienzimáticos/química
Multimerização Proteica
[Mh] Termos MeSH secundário: DNA/biossíntese
DNA/genética
DNA Helicases/genética
DNA Helicases/metabolismo
DNA Polimerase I/genética
DNA Polimerase I/metabolismo
Replicação do DNA/fisiologia
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Células HEK293
Seres Humanos
Complexos Multienzimáticos/genética
Complexos Multienzimáticos/metabolismo
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Multienzyme Complexes); 0 (WDHD1 protein, human); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I); EC 3.6.4.- (DNA Helicases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170616
[Lr] Data última revisão:
170616
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.758524


  9 / 2958 MEDLINE  
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[PMID]:28334750
[Au] Autor:Feng X; Hsu SJ; Kasbek C; Chaiken M; Price CM
[Ad] Endereço:Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45230, USA.
[Ti] Título:CTC1-mediated C-strand fill-in is an essential step in telomere length maintenance.
[So] Source:Nucleic Acids Res;45(8):4281-4293, 2017 May 05.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To prevent progressive telomere shortening as a result of conventional DNA replication, new telomeric DNA must be added onto the chromosome end. The de novo DNA synthesis involves elongation of the G-rich strand of the telomere by telomerase. In human cells, the CST complex (CTC1-STN1-TEN1) also functions in telomere replication. CST first aids in duplication of the telomeric dsDNA. Then after telomerase has extended the G-rich strand, CST facilitates fill-in synthesis of the complementary C-strand. Here, we analyze telomere structure after disruption of human CTC1 and demonstrate that functional CST is essential for telomere length maintenance due to its role in mediating C-strand fill-in. Removal of CTC1 results in elongation of the 3΄ overhang on the G-rich strand. This leads to accumulation of RPA and telomeric DNA damage signaling. G-overhang length increases with time after CTC1 disruption and at early times net G-strand growth is apparent, indicating telomerase-mediated G-strand extension. In contrast, C-strand length decreases continuously, indicating a deficiency in C-strand fill-in synthesis. The lack of C-strand maintenance leads to gradual shortening of the telomeric dsDNA, similar to that observed in cells lacking telomerase. Thus, telomerase-mediated G-strand extension and CST-mediated C-strand fill-in are equally important for telomere length maintenance.
[Mh] Termos MeSH primário: DNA/química
Telomerase/genética
Homeostase do Telômero
Proteínas de Ligação a Telômeros/genética
Telômero/metabolismo
[Mh] Termos MeSH secundário: DNA/genética
DNA/metabolismo
Dano ao DNA
DNA Polimerase I/genética
DNA Polimerase I/metabolismo
Replicação do DNA
Deleção de Genes
Regulação da Expressão Gênica
Células HCT116
Células HEK293
Seres Humanos
Telomerase/metabolismo
Telômero/ultraestrutura
Encurtamento do Telômero
Proteínas de Ligação a Telômeros/deficiência
Proteínas de Ligação a Telômeros/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ctc1 protein, human); 0 (Stn1 protein, human); 0 (Telomere-Binding Proteins); 0 (Ten1 protein, human); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx125


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[PMID]:28301743
[Au] Autor:Burgers PMJ; Kunkel TA
[Ad] Endereço:Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110; email: burgers@biochem.wustl.edu.
[Ti] Título:Eukaryotic DNA Replication Fork.
[So] Source:Annu Rev Biochem;86:417-438, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This review focuses on the biogenesis and composition of the eukaryotic DNA replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork. Physical and genetic methodologies aimed at understanding these processes are discussed. The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork. DNA polymerases α and δ carry out the initiation of Okazaki fragment synthesis and its elongation and maturation, respectively. This review also discusses alternative proposals, including cellular processes during which alternative forks may be utilized, and new biochemical studies with purified proteins that are aimed at reconstituting leading and lagging strand DNA synthesis separately and as an integrated replication fork.
[Mh] Termos MeSH primário: DNA Helicases/genética
DNA Polimerase II/genética
Replicação do DNA
DNA/genética
Células Eucarióticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Ciclo Celular/genética
Proteínas de Ciclo Celular/metabolismo
DNA/metabolismo
DNA Helicases/metabolismo
DNA Polimerase I/genética
DNA Polimerase I/metabolismo
DNA Polimerase II/metabolismo
DNA Polimerase III/genética
DNA Polimerase III/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Células Eucarióticas/citologia
Seres Humanos
Proteínas de Manutenção de Minicromossomo/genética
Proteínas de Manutenção de Minicromossomo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (CDC45 protein, human); 0 (Cell Cycle Proteins); 0 (DNA-Binding Proteins); 0 (GINS1 protein, human); 0 (Okazaki fragments); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase I); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (Minichromosome Maintenance Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-061516-044709



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