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Pesquisa : D08.811.277.352.355.325.350 [Categoria DeCS]
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  1 / 533 MEDLINE  
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[PMID]:28450457
[Au] Autor:Nagarajan P; Prevost CT; Stein A; Kasimer R; Kalifa L; Sia EA
[Ad] Endereço:Department of Biology, University of Rochester, New York 14627.
[Ti] Título:Roles for the Rad27 Flap Endonuclease in Mitochondrial Mutagenesis and Double-Strand Break Repair in .
[So] Source:Genetics;206(2):843-857, 2017 06.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The structure-specific nuclease, Rad27p/FEN1, plays a crucial role in DNA repair and replication mechanisms in the nucleus. Genetic assays using the mutant have shown altered rates of DNA recombination, microsatellite instability, and point mutation in mitochondria. In this study, we examined the role of Rad27p in mitochondrial mutagenesis and double-strand break (DSB) repair in Our findings show that Rad27p is essential for efficient mitochondrial DSB repair by a pathway that generates deletions at a region flanked by direct repeat sequences. Mutant analysis suggests that both exonuclease and endonuclease activities of Rad27p are required for its role in mitochondrial DSB repair. In addition, we found that the nuclease activities of Rad27p are required for the prevention of mitochondrial DNA (mtDNA) point mutations, and in the generation of spontaneous mtDNA rearrangements. Overall, our findings underscore the importance of Rad27p in the maintenance of mtDNA, and demonstrate that it participates in multiple DNA repair pathways in mitochondria, unlinked to nuclear phenotypes.
[Mh] Termos MeSH primário: Quebras de DNA de Cadeia Dupla
Reparo do DNA/genética
DNA Mitocondrial/genética
Endonucleases Flap/genética
Proteínas de Saccharomyces cerevisiae/genética
[Mh] Termos MeSH secundário: Proteínas de Ligação a DNA/genética
Mutagênese/genética
Mutação
Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (DNA, Mitochondrial); 0 (DNA-Binding Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 3.1.- (Flap Endonucleases); EC 3.1.11.5 (RAD27 protein, S cerevisiae)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.116.195149


  2 / 533 MEDLINE  
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[PMID]:28682061
[Au] Autor:Shaw SJ; Finger LD; Grasby JA
[Ad] Endereço:Centre for Chemical Biology, Department of Chemistry, Krebs Institute, University of Sheffield , Sheffield S3 7HF, U.K.
[Ti] Título:Human Exonuclease 1 Threads 5'-Flap Substrates through Its Helical Arch.
[So] Source:Biochemistry;56(29):3704-3707, 2017 Jul 25.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human exonuclease 1 (hEXO1) is a member of the 5'-nuclease superfamily and plays important roles in DNA repair. Along with acting as a 5'-exonuclease on blunt, gapped, nicked, and 3'-overhang DNAs, hEXO1 can also act as an endonuclease removing protruding 5'-single-stranded flaps from duplex ends. How hEXO1 and related 5'-nuclease human flap endonuclease 1 (hFEN1) are specific for discontinuous DNA substrates like 5'-flaps has been controversial. Here we report the first functional data that imply that hEXO1 threads the 5'-flap through a hole in the protein known as the helical arch, thereby excluding reactions of continuous single strands. Conjugation of bulky 5'-streptavidin that would "block" threading through the arch drastically slowed the hEXO1 reaction. In contrast, addition of streptavidin to a preformed hEXO1 5'-biotin flap DNA complex trapped a portion of the substrate in a highly reactive threaded conformation. However, another fraction behaves as if it were "blocked" and decayed very slowly, implying there were both threaded and unthreaded forms of the substrate present. The reaction of an unmodified hEXO1-flap DNA complex did not exhibit marked biphasic kinetics, suggesting a fast re-equilibration occurs that produces more threaded substrate when some decays. The finding that a threading mechanism like that used by hFEN1 is also used by hEXO1 unifies the mode of operation for members of the 5'-nuclease superfamily that act on discontinuous substrates. As with hFEN1, intrinsic disorder of the arch region of the protein may explain how flaps can be threaded without a need for a coupled energy source.
[Mh] Termos MeSH primário: Enzimas Reparadoras do DNA/química
Reparo do DNA
DNA/química
Exodesoxirribonucleases/química
Modelos Químicos
[Mh] Termos MeSH secundário: Endonucleases Flap/química
Seres Humanos
Cinética
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.1.- (EXO1 protein, human); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (Flap Endonucleases); EC 3.1.11.- (FEN1 protein, human); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170727
[Lr] Data última revisão:
170727
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00507


  3 / 533 MEDLINE  
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[PMID]:28678842
[Au] Autor:Kaniak-Golik A; Kuberska R; Dzierzbicki P; Sledziewska-Gojska E
[Ad] Endereço:Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
[Ti] Título:Activation of Dun1 in response to nuclear DNA instability accounts for the increase in mitochondrial point mutations in Rad27/FEN1 deficient S. cerevisiae.
[So] Source:PLoS One;12(7):e0180153, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rad27/FEN1 nuclease that plays important roles in the maintenance of DNA stability in the nucleus has recently been shown to reside in mitochondria. Accordingly, it has been established that Rad27 deficiency causes increased mutagenesis, but decreased microsatellite instability and homologous recombination in mitochondria. Our current analysis of mutations leading to erythromycin resistance indicates that only some of them arise in mitochondrial DNA and that the GC→AT transition is a hallmark of the mitochondrial mutagenesis in rad27 null background. We also show that the mitochondrial mutator phenotype resulting from Rad27 deficiency entirely depends on the DNA damage checkpoint kinase Dun1. DUN1 inactivation suppresses the mitochondrial mutator phenotype caused by Rad27 deficiency and this suppression is eliminated at least in part by subsequent deletion of SML1 encoding a repressor of ribonucleotide reductase. We conclude that Rad27 deficiency causes a mitochondrial mutator phenotype via activation of DNA damage checkpoint kinase Dun1 and that a Dun1-mediated increase of dNTP pools contributes to this phenomenon. These results point to the nuclear DNA instability as the source of mitochondrial mutagenesis. Consistently, we show that mitochondrial mutations occurring more frequently in yeast devoid of Rrm3, a DNA helicase involved in rDNA replication, are also dependent on Dun1. In addition, we have established that overproduction of Exo1, which suppresses DNA damage sensitivity and replication stress in nuclei of Rad27 deficient cells, but does not enter mitochondria, suppresses the mitochondrial mutagenesis. Exo1 overproduction restores also a great part of allelic recombination and microsatellite instability in mitochondria of Rad27 deficient cells. In contrast, the overproduction of Exo1 does not influence mitochondrial direct-repeat mediated deletions in rad27 null background, pointing to this homologous recombination pathway as the direct target of Rad27 activity in mitochondria.
[Mh] Termos MeSH primário: Acetiltransferases/genética
Proteínas de Ciclo Celular/fisiologia
Endonucleases Flap/genética
Proteínas de Membrana/genética
Proteínas Serina-Treonina Quinases/fisiologia
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/fisiologia
Saccharomyces cerevisiae/enzimologia
[Mh] Termos MeSH secundário: Acetiltransferases/metabolismo
Núcleo Celular/enzimologia
Núcleo Celular/genética
Dano ao DNA
DNA Fúngico/genética
DNA Mitocondrial/genética
Ativação Enzimática
Endonucleases Flap/metabolismo
Técnicas de Inativação de Genes
Instabilidade Genômica
Proteínas de Membrana/metabolismo
Mutagênese
Mutação Puntual
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (DNA, Fungal); 0 (DNA, Mitochondrial); 0 (Membrane Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.3.1.- (Acetyltransferases); EC 2.3.1.- (ELO2 protein, S cerevisiae); EC 2.7.1.- (DUN1 protein, S cerevisiae); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.1.- (Flap Endonucleases); EC 3.1.11.5 (RAD27 protein, S cerevisiae)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170706
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180153


  4 / 533 MEDLINE  
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[PMID]:28628639
[Au] Autor:Ward TA; McHugh PJ; Durant ST
[Ad] Endereço:AstraZeneca, Innovative Medicines and Early Development Biotech Unit, Oncology Bioscience, Alderley Park, Macclesfield, Cheshire, United Kingdom.
[Ti] Título:Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes.
[So] Source:PLoS One;12(6):e0179278, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response. This sensitivity is due to a synthetic lethal interaction between FEN1 and MRE11A, which is often mutated in MSI cancers through instabilities at a poly(T) microsatellite repeat. Disruption of ATM is similarly synthetic lethal with FEN1 inhibition, suggesting that disruption of FEN1 function leads to the accumulation of DNA double-strand breaks. These are likely a result of the accumulation of aberrant replication forks, that accumulate as a consequence of a failure in Okazaki fragment maturation, as inhibition of FEN1 is toxic in cells disrupted for the Fanconi anemia pathway and post-replication repair. Furthermore, RAD51 foci accumulate as a consequence of FEN1 inhibition and the toxicity of FEN1 inhibitors increases in cells disrupted for the homologous recombination pathway, suggesting a role for homologous recombination in the resolution of damage induced by FEN1 inhibition. Finally, FEN1 appears to be required for the repair of damage induced by olaparib and cisplatin within the Fanconi anemia pathway, and may play a role in the repair of damage associated with its own disruption.
[Mh] Termos MeSH primário: Reparo do DNA/efeitos dos fármacos
Endonucleases Flap/metabolismo
Hidroxiureia/toxicidade
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Cisplatino/toxicidade
DNA/efeitos dos fármacos
DNA/metabolismo
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Replicação do DNA/efeitos dos fármacos
Proteínas de Ligação a DNA/antagonistas & inibidores
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Regulação para Baixo/efeitos dos fármacos
Endonucleases Flap/antagonistas & inibidores
Endonucleases Flap/genética
Seres Humanos
Hidroxiureia/química
Proteína Homóloga a MRE11
Instabilidade de Microssatélites/efeitos dos fármacos
Mutação
Ftalazinas/toxicidade
Piperazinas/toxicidade
Inibidores de Poli(ADP-Ribose) Polimerases/toxicidade
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Rad51 Recombinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (MRE11A protein, human); 0 (Okazaki fragments); 0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (RNA, Small Interfering); 9007-49-2 (DNA); EC 2.7.7.- (Rad51 Recombinase); EC 3.1.- (Flap Endonucleases); EC 3.1.- (MRE11 Homologue Protein); EC 3.1.11.- (FEN1 protein, human); Q20Q21Q62J (Cisplatin); WOH1JD9AR8 (olaparib); X6Q56QN5QC (Hydroxyurea)
[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:170620
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179278


  5 / 533 MEDLINE  
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[PMID]:28416706
[Au] Autor:Burkhart BW; Cubonova L; Heider MR; Kelman Z; Reeve JN; Santangelo TJ
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, USA.
[Ti] Título:The GAN Exonuclease or the Flap Endonuclease Fen1 and RNase HII Are Necessary for Viability of Thermococcus kodakarensis.
[So] Source:J Bacteriol;199(13), 2017 Jul 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many aspects of and factors required for DNA replication are conserved across all three domains of life, but there are some significant differences surrounding lagging-strand synthesis. In , a 5'-to-3' exonuclease, related to both bacterial RecJ and eukaryotic Cdc45, that associates with the replisome specifically through interactions with GINS was identified and designated GAN (for INS- ssociated uclease). Despite the presence of a well-characterized flap endonuclease (Fen1), it was hypothesized that GAN might participate in primer removal during Okazaki fragment maturation, and as a Cdc45 homologue, GAN might also be a structural component of an archaeal CMG (Cdc45, MCM, and GINS) replication complex. We demonstrate here that, individually, either Fen1 or GAN can be deleted, with no discernible effects on viability and growth. However, deletion of both Fen1 and GAN was not possible, consistent with both enzymes catalyzing the same step in primer removal from Okazaki fragments RNase HII has also been proposed to participate in primer processing during Okazaki fragment maturation. Strains with both Fen1 and RNase HII deleted grew well. GAN activity is therefore sufficient for viability in the absence of both RNase HII and Fen1, but it was not possible to construct a strain with both RNase HII and GAN deleted. Fen1 alone is therefore insufficient for viability in the absence of both RNase HII and GAN. The ability to delete GAN demonstrates that GAN is not required for the activation or stability of the archaeal MCM replicative helicase. The mechanisms used to remove primer sequences from Okazaki fragments during lagging-strand DNA replication differ in the biological domains. Bacteria use the exonuclease activity of DNA polymerase I, whereas eukaryotes and archaea encode a flap endonuclease (Fen1) that cleaves displaced primer sequences. RNase HII and the GINS-associated exonuclease GAN have also been hypothesized to assist in primer removal in Here we demonstrate that in , either Fen1 or GAN activity is sufficient for viability. Furthermore, GAN can support growth in the absence of both Fen1 and RNase HII, but Fen1 and RNase HII are required for viability in the absence of GAN.
[Mh] Termos MeSH primário: Exorribonucleases/metabolismo
Endonucleases Flap/metabolismo
Regulação Bacteriana da Expressão Gênica/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Thermococcus/enzimologia
[Mh] Termos MeSH secundário: Exorribonucleases/genética
Endonucleases Flap/genética
Deleção de Genes
Genoma Bacteriano
Viabilidade Microbiana/genética
Thermococcus/genética
Thermococcus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.- (Exoribonucleases); EC 3.1.- (Flap Endonucleases); EC 3.1.13.2 (exoribonuclease H)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE


  6 / 533 MEDLINE  
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[PMID]:28159842
[Au] Autor:Liu B; Hu J; Wang J; Kong D
[Ad] Endereço:From the Peking-Tsinghua Center for Life Sciences, The National Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China.
[Ti] Título:Direct Visualization of RNA-DNA Primer Removal from Okazaki Fragments Provides Support for Flap Cleavage and Exonucleolytic Pathways in Eukaryotic Cells.
[So] Source:J Biol Chem;292(12):4777-4788, 2017 Mar 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During DNA replication in eukaryotic cells, short single-stranded DNA segments known as Okazaki fragments are first synthesized on the lagging strand. The Okazaki fragments originate from ∼35-nucleotide-long RNA-DNA primers. After Okazaki fragment synthesis, these primers must be removed to allow fragment joining into a continuous lagging strand. To date, the models of enzymatic machinery that removes the RNA-DNA primers have come almost exclusively from biochemical reconstitution studies and some genetic interaction assays, and there is little direct evidence to confirm these models. One obstacle to elucidating Okazaki fragment processing has been the lack of methods that can directly examine primer removal In this study, we developed an electron microscopy assay that can visualize nucleotide flap structures on DNA replication forks in fission yeast ( ). With this assay, we first demonstrated the generation of flap structures during Okazaki fragment processing The mean and median lengths of the flaps in wild-type cells were ∼51 and ∼41 nucleotides, respectively. We also used yeast mutants to investigate the impact of deleting key DNA replication nucleases on these flap structures. Our results provided direct evidence for a previously proposed flap cleavage pathway and the critical function of Dna2 and Fen1 in cleaving these flaps. In addition, we found evidence for another previously proposed exonucleolytic pathway involving RNA-DNA primer digestion by exonucleases RNase H2 and Exo1. Taken together, our observations suggest a dual mechanism for Okazaki fragment maturation in lagging strand synthesis and establish a new strategy for interrogation of this fascinating process.
[Mh] Termos MeSH primário: Primers do DNA/metabolismo
DNA/metabolismo
Endodesoxirribonucleases/metabolismo
Endonucleases Flap/metabolismo
RNA/metabolismo
Proteínas de Schizosaccharomyces pombe/metabolismo
Schizosaccharomyces/citologia
Transdução de Sinais
[Mh] Termos MeSH secundário: DNA/análise
DNA/genética
DNA/ultraestrutura
Primers do DNA/análise
Primers do DNA/genética
Replicação do DNA
DNA Fúngico/análise
DNA Fúngico/genética
DNA Fúngico/metabolismo
Endodesoxirribonucleases/análise
Endodesoxirribonucleases/genética
Endonucleases Flap/análise
Endonucleases Flap/genética
Mutação
RNA/análise
RNA/genética
Schizosaccharomyces/genética
Schizosaccharomyces/metabolismo
Proteínas de Schizosaccharomyces pombe/análise
Proteínas de Schizosaccharomyces pombe/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Primers); 0 (DNA, Fungal); 0 (Okazaki fragments); 0 (RNA primers); 0 (Schizosaccharomyces pombe Proteins); 63231-63-0 (RNA); 9007-49-2 (DNA); EC 3.1.- (Dna2 protein, S pombe); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Flap Endonucleases); EC 3.1.25.- (Rad2 protein, S pombe)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.758599


  7 / 533 MEDLINE  
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[PMID]:28096179
[Au] Autor:Princz LN; Wild P; Bittmann J; Aguado FJ; Blanco MG; Matos J; Pfander B
[Ad] Endereço:Max Planck Institute of Biochemistry, DNA Replication and Genome Integrity, Martinsried, Germany.
[Ti] Título:Dbf4-dependent kinase and the Rtt107 scaffold promote Mus81-Mms4 resolvase activation during mitosis.
[So] Source:EMBO J;36(5):664-678, 2017 Mar 01.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA repair by homologous recombination is under stringent cell cycle control. This includes the last step of the reaction, disentanglement of DNA joint molecules (JMs). Previous work has established that JM resolving nucleases are activated specifically at the onset of mitosis. In case of budding yeast Mus81-Mms4, this cell cycle stage-specific activation is known to depend on phosphorylation by CDK and Cdc5 kinases. Here, we show that a third cell cycle kinase, Cdc7-Dbf4 (DDK), targets Mus81-Mms4 in conjunction with Cdc5-both kinases bind to as well as phosphorylate Mus81-Mms4 in an interdependent manner. Moreover, DDK-mediated phosphorylation of Mms4 is strictly required for Mus81 activation in mitosis, establishing DDK as a novel regulator of homologous recombination. The scaffold protein Rtt107, which binds the Mus81-Mms4 complex, interacts with Cdc7 and thereby targets DDK and Cdc5 to the complex enabling full Mus81 activation. Therefore, Mus81 activation in mitosis involves at least three cell cycle kinases, CDK, Cdc5 and DDK Furthermore, tethering of the kinases in a stable complex with Mus81 is critical for efficient JM resolution.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Proteínas de Ligação a DNA/metabolismo
Endonucleases/metabolismo
Endonucleases Flap/metabolismo
Mitose
Proteínas Nucleares/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/fisiologia
[Mh] Termos MeSH secundário: Ativação Enzimática
Saccharomyces cerevisiae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (DNA-Binding Proteins); 0 (Nuclear Proteins); 0 (RTT107 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.- (CDC7 protein, S cerevisiae); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.21 (CDC5 protein, S cerevisiae); EC 3.1.- (Endonucleases); EC 3.1.- (Flap Endonucleases); EC 3.1.- (MUS81 protein, S cerevisiae); EC 3.1.22.- (MMS4 protein, S cerevisiae)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201694831


  8 / 533 MEDLINE  
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[PMID]:27849570
[Au] Autor:Li B; Reddy S; Comai L
[Ad] Endereço:Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
[Ti] Título:The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation.
[So] Source:Mol Cell Biol;37(3), 2017 Feb 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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.
[Mh] Termos MeSH primário: DNA Polimerase III/metabolismo
Replicação do DNA
Endonucleases Flap/metabolismo
Helicase da Síndrome de Werner/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
DNA/biossíntese
Células HeLa
Homeostase
Seres Humanos
Polimerização
Domínios Proteicos
RecQ Helicases/metabolismo
Sequências Repetitivas de Ácido Nucleico/genética
Especificidade por Substrato
Telômero/metabolismo
Helicase da Síndrome de Werner/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase III); EC 3.1.- (Flap Endonucleases); EC 3.1.11.- (FEN1 protein, human); EC 3.6.1.- (Bloom syndrome protein); EC 3.6.4.12 (RecQ Helicases); EC 3.6.4.12 (Werner Syndrome Helicase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161117
[St] Status:MEDLINE


  9 / 533 MEDLINE  
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[PMID]:27694478
[Au] Autor:Zhou L; Dai H; Wu J; Zhou M; Yuan H; Du J; Yang L; Wu X; Xu H; Hua Y; Xu J; Zheng L; Shen B
[Ad] Endereço:College of Life Sciences and Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
[Ti] Título:Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development.
[So] Source:FASEB J;31(1):132-147, 2017 Jan.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 in DNA repair as well as Okazaki fragment maturation. However, the biologic significance of FEN1 phosphorylation in response to DNA damage remains unknown. Here, we report an in vivo role for FEN1 phosphorylation, using a mouse line carrying S187A FEN1, which abolishes FEN1 phosphorylation. Although S187A mouse embryonic fibroblast cells showed normal proliferation under low oxygen levels (2%), the mutant cells accumulated oxidative DNA damage, activated DNA damage checkpoints, and showed G -phase arrest at atmospheric oxygen levels (21%). This suggests an essential role for FEN1 phosphorylation in repairing oxygen-induced DNA damage and maintaining proper cell cycle progression. Consistently, the mutant cardiomyocytes showed G -phase arrest due to activation of the p53-mediated DNA damage response at the neonatal stage, which reduces the proliferation potential of the cardiomyocytes and impairs heart development. Nearly 50% of newborns with the S187A mutant died in the first week due to failure to undergo the peroxisome proliferator-activated receptor signaling-dependent switch from glycolysis to fatty acid oxidation. The adult mutant mice developed dilated hearts and showed significantly shorter life spans. Altogether, our results reveal an important role of FEN1 phosphorylation to counteract oxygen-induced stress in the heart during the fetal-to-neonatal transition.-Zhou, L., Dai, H., Wu, J., Zhou, M., Yuan, H., Du, J., Yang, L., Wu, X., Xu, H., Hua, Y., Xu, J., Zheng, L., Shen, B. Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development.
[Mh] Termos MeSH primário: Endonucleases Flap/metabolismo
Regulação da Expressão Gênica no Desenvolvimento/fisiologia
Coração/crescimento & desenvolvimento
Oxigênio
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Dano ao DNA
Feminino
Fibroblastos
Endonucleases Flap/genética
Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia
Coração/embriologia
Masculino
Camundongos
Estresse Oxidativo
Fosforilação
Mutação Puntual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.- (Fen1 protein, mouse); EC 3.1.- (Flap Endonucleases); S88TT14065 (Oxygen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161004
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201600631R


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[PMID]:27270424
[Au] Autor:Sun H; He L; Wu H; Pan F; Wu X; Zhao J; Hu Z; Sekhar C; Li H; Zheng L; Chen H; Shen BH; Guo Z
[Ad] Endereço:Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
[Ti] Título:The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation.
[So] Source:Oncogene;36(2):194-207, 2017 Jan 12.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Flap endonuclease-1 (FEN1) is a multifunctional, structure-specific nuclease that has a critical role in maintaining human genome stability. FEN1 mutations have been detected in human cancer specimens and have been suggested to cause genomic instability and cancer predisposition. However, the exact relationship between FEN1 deficiency and cancer susceptibility remains unclear. In the current work, we report a novel colorectal cancer-associated FEN1 mutation, L209P. This mutant protein lacks the FEN, exonuclease (EXO) and gap endonuclease (GEN) activities of FEN1 but retains DNA-binding affinity. The L209P FEN1 variant interferes with the function of the wild-type FEN1 enzyme in a dominant-negative manner and impairs long-patch base excision repair in vitro and in vivo. Expression of L209P FEN1 sensitizes cells to DNA damage, resulting in endogenous genomic instability and cellular transformation, as well as tumor growth in a mouse xenograft model. These data indicate that human cancer-associated genetic alterations in the FEN1 gene can contribute substantially to cancer development.
[Mh] Termos MeSH primário: Transformação Celular Neoplásica/genética
Neoplasias Colorretais/genética
Reparo do DNA
Endonucleases Flap/genética
Mutação
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular
Transformação Celular Neoplásica/metabolismo
Neoplasias Colorretais/metabolismo
Dano ao DNA
Endonucleases Flap/metabolismo
Instabilidade Genômica
Seres Humanos
Camundongos
Transplante de Neoplasias
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.- (Flap Endonucleases); EC 3.1.11.- (FEN1 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.188



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