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  1 / 2098 MEDLINE  
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[PMID]:29281621
[Au] Autor:Tellier-Lebegue C; Dizet E; Ma E; Veaute X; Coïc E; Charbonnier JB; Maloisel L
[Ad] Endereço:I2BC, CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, Gif-sur-Yvette, France.
[Ti] Título:The translesion DNA polymerases Pol ζ and Rev1 are activated independently of PCNA ubiquitination upon UV radiation in mutants of DNA polymerase δ.
[So] Source:PLoS Genet;13(12):e1007119, 2017 12.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Replicative DNA polymerases cannot insert efficiently nucleotides at sites of base lesions. This function is taken over by specialized translesion DNA synthesis (TLS) polymerases to allow DNA replication completion in the presence of DNA damage. In eukaryotes, Rad6- and Rad18-mediated PCNA ubiquitination at lysine 164 promotes recruitment of TLS polymerases, allowing cells to efficiently cope with DNA damage. However, several studies showed that TLS polymerases can be recruited also in the absence of PCNA ubiquitination. We hypothesized that the stability of the interactions between DNA polymerase δ (Pol δ) subunits and/or between Pol δ and PCNA at the primer/template junction is a crucial factor to determine the requirement of PCNA ubiquitination. To test this hypothesis, we used a structural mutant of Pol δ in which the interaction between Pol3 and Pol31 is inhibited. We found that in yeast, rad18Δ-associated UV hypersensitivity is suppressed by pol3-ct, a mutant allele of the POL3 gene that encodes the catalytic subunit of replicative Pol δ. pol3-ct suppressor effect was specifically dependent on the Rev1 and Pol ζ TLS polymerases. This result strongly suggests that TLS polymerases could rely much less on PCNA ubiquitination when Pol δ interaction with PCNA is partially compromised by mutations. In agreement with this model, we found that the pol3-FI allele suppressed rad18Δ-associated UV sensitivity as observed for pol3-ct. This POL3 allele carries mutations within a putative PCNA Interacting Peptide (PIP) motif. We then provided molecular and genetic evidence that this motif could contribute to Pol δ-PCNA interaction indirectly, although it is not a bona fide PIP. Overall, our results suggest that the primary role of PCNA ubiquitination is to allow TLS polymerases to outcompete Pol δ for PCNA access upon DNA damage.
[Mh] Termos MeSH primário: DNA Polimerase III/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
DNA/genética
DNA/metabolismo
Dano ao DNA
DNA Polimerase III/genética
Reparo do DNA
Replicação do DNA
DNA Polimerase Dirigida por DNA/genética
DNA Polimerase Dirigida por DNA/metabolismo
Modelos Genéticos
Mutação
Nucleotidiltransferases/genética
Nucleotidiltransferases/metabolismo
Antígeno Nuclear de Célula em Proliferação/genética
Antígeno Nuclear de Célula em Proliferação/metabolismo
Ligação Proteica
Saccharomyces cerevisiae
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Ubiquitinação
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proliferating Cell Nuclear Antigen); 0 (Saccharomyces cerevisiae Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (DNA polymerase zeta); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.- (REV1 protein, S cerevisiae); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007119


  2 / 2098 MEDLINE  
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[PMID]:29033319
[Au] Autor:Gan H; Yu C; Devbhandari S; Sharma S; Han J; Chabes A; Remus D; Zhang Z
[Ad] Endereço:Institute for Cancer Genetics and Department of Pediatrics and Genetics and Development, Columbia University, New York, NY 10032.
[Ti] Título:Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress.
[So] Source:Mol Cell;68(2):446-455.e3, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Quinase do Ponto de Checagem 2/metabolismo
DNA Polimerase III/metabolismo
DNA Polimerase II/metabolismo
Replicação do DNA/fisiologia
DNA Fúngico/biossíntese
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Ciclo Celular/genética
Quinase do Ponto de Checagem 2/genética
DNA Polimerase II/genética
DNA Polimerase III/genética
DNA Fúngico/genética
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (DNA, Fungal); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.12.1 (RAD53 protein, S cerevisiae); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


  3 / 2098 MEDLINE  
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[PMID]:28976792
[Au] Autor:Wang X; Sun CL; Hageman L; Smith K; Singh P; Desai S; Hawkins DS; Hudson MM; Mascarenhas L; Neglia JP; Oeffinger KC; Ritchey AK; Robison LL; Villaluna D; Landier W; Bhatia S
[Ad] Endereço:Xuexia Wang, University of North Texas, Denton, TX; Can-Lan Sun, City of Hope, Duarte; Leo Mascarenhas, Children's Hospital Los Angeles, University of Southern California, Los Angeles; Doojduen Villaluna, Children's Oncology Group, Monrovia, CA; Lindsey Hageman, Kandice Smith, Purnima Singh, Wendy L
[Ti] Título:Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study.
[So] Source:J Clin Oncol;35(32):3688-3696, 2017 Nov 10.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.
[Mh] Termos MeSH primário: Adultos Sobreviventes de Eventos Adversos na Infância
Neoplasias do Sistema Nervoso Central/etiologia
Neoplasias do Sistema Nervoso Central/genética
Predisposição Genética para Doença
Neoplasias Induzidas por Radiação/etiologia
Neoplasias Induzidas por Radiação/genética
Neoplasias/radioterapia
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adolescente
Adulto
Fatores Etários
Estudos de Casos e Controles
DNA Ligase Dependente de ATP
DNA Polimerase III
Proteínas de Ligação a DNA
Endonucleases
Feminino
Genes BRCA2
Seres Humanos
Masculino
Medição de Risco
Fatores de Risco
Proteína Supressora de Tumor p53
Proteína 1 Complementadora Cruzada de Reparo de Raio-X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (LIG4 protein, human); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 0 (X-ray Repair Cross Complementing Protein 1); 0 (XRCC1 protein, human); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (POLD1 protein, human); EC 3.1.- (ERCC1 protein, human); EC 3.1.- (Endonucleases); EC 6.5.1.1 (DNA Ligase ATP)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2017.74.7444


  4 / 2098 MEDLINE  
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[PMID]:28934474
[Au] Autor:Liu D; Frederiksen JH; Liberti SE; Lützen A; Keijzers G; Pena-Diaz J; Rasmussen LJ
[Ad] Endereço:Center for Healthy Aging, University of Copenhagen, Denmark.
[Ti] Título:Human DNA polymerase delta double-mutant D316A;E318A interferes with DNA mismatch repair in vitro.
[So] Source:Nucleic Acids Res;45(16):9427-9440, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA mismatch repair (MMR) is a highly-conserved DNA repair mechanism, whose primary role is to remove DNA replication errors preventing them from manifesting as mutations, thereby increasing the overall genome stability. Defects in MMR are associated with increased cancer risk in humans and other organisms. Here, we characterize the interaction between MMR and a proofreading-deficient allele of the human replicative DNA polymerase delta, PolδD316A;E318A, which has a higher capacity for strand displacement DNA synthesis than wild type Polδ. Human cell lines overexpressing PolδD316A;E318A display a mild mutator phenotype, while nuclear extracts of these cells exhibit reduced MMR activity in vitro, and these defects are complemented by overexpression or addition of exogenous human Exonuclease 1 (EXO1). By contrast, another proofreading-deficient mutant, PolδD515V, which has a weaker strand displacement activity, does not decrease the MMR activity as significantly as PolδD316A;E318A. In addition, PolδD515V does not increase the mutation frequency in MMR-proficient cells. Based on our findings, we propose that the proofreading activity restricts the strand displacement activity of Polδ in MMR. This contributes to maintain the nicks required for EXO1 entry, and in this manner ensures the dominance of the EXO1-dependent MMR pathway.
[Mh] Termos MeSH primário: Reparo de Erro de Pareamento de DNA
DNA Polimerase III/metabolismo
Mutação
[Mh] Termos MeSH secundário: Metilação de DNA/efeitos dos fármacos
DNA Polimerase III/genética
Enzimas Reparadoras do DNA/genética
Enzimas Reparadoras do DNA/metabolismo
Exodesoxirribonucleases/genética
Exodesoxirribonucleases/metabolismo
Células HeLa
Seres Humanos
Metilnitronitrosoguanidina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
12H3O2UGSF (Methylnitronitrosoguanidine); EC 2.7.7.- (DNA Polymerase III); EC 3.1.- (EXO1 protein, human); EC 3.1.- (Exodeoxyribonucleases); EC 6.5.1.- (DNA Repair Enzymes)
[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/gkx611


  5 / 2098 MEDLINE  
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[PMID]:28846956
[Au] Autor:Nebot-Bral L; Brandao D; Verlingue L; Rouleau E; Caron O; Despras E; El-Dakdouki Y; Champiat S; Aoufouchi S; Leary A; Marabelle A; Malka D; Chaput N; Kannouche PL
[Ad] Endereço:UMR8200 - CNRS, Stabilité Génétique et Oncogenèse, France; Gustave Roussy Cancer Campus, F-94805, Villejuif, France; Université Paris Saclay, Paris Sud - Orsay, F-91400, France.
[Ti] Título:Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine.
[So] Source:Eur J Cancer;84:290-303, 2017 Oct.
[Is] ISSN:1879-0852
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/genética
Biomarcadores Tumorais/genética
Imunoterapia/métodos
Mutação
Neoplasias/genética
Neoplasias/terapia
Medicina de Precisão/métodos
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/imunologia
Biomarcadores Tumorais/imunologia
Reparo de Erro de Pareamento de DNA
Análise Mutacional de DNA
DNA Polimerase II/genética
DNA Polimerase II/metabolismo
DNA Polimerase III/genética
DNA Polimerase III/metabolismo
Predisposição Genética para Doença
Seres Humanos
Instabilidade de Microssatélites
Terapia de Alvo Molecular
Neoplasias/imunologia
Neoplasias/patologia
Fenótipo
Proteínas de Ligação a Poli-ADP-Ribose
Valor Preditivo dos Testes
Evasão Tumoral
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Biomarkers, Tumor); 0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (POLD1 protein, human); EC 2.7.7.7 (POLE protein, human)
[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:170829
[St] Status:MEDLINE


  6 / 2098 MEDLINE  
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[PMID]:28834716
[Au] Autor:Purohit A; England JK; Douma LG; Tondnevis F; Bloom LB; Levitus M
[Ad] Endereço:School of Molecular Sciences and Biodesign Institute, Arizona State University, Tempe, Arizona.
[Ti] Título:Electrostatic Interactions at the Dimer Interface Stabilize the E. coli ß Sliding Clamp.
[So] Source:Biophys J;113(4):794-804, 2017 Aug 22.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sliding clamps are ring-shaped oligomeric proteins that encircle DNA and associate with DNA polymerases for processive DNA replication. The dimeric Escherichia coli ß-clamp is closed in solution but must adopt an open conformation to be assembled onto DNA by a clamp loader. To determine what factors contribute to the stability of the dimer interfaces in the closed conformation and how clamp dynamics contribute to formation of the open conformation, we identified conditions that destabilized the dimer and measured the effects of these conditions on clamp dynamics. We characterized the role of electrostatic interactions in stabilizing the ß-clamp interface. Increasing salt concentration results in decreased dimer stability and faster subunit dissociation kinetics. The equilibrium dissociation constant of the dimeric clamp varies with salt concentration as predicted by simple charge-screening models, indicating that charged amino acids contribute to the remarkable stability of the interface at physiological salt concentrations. Mutation of a charged residue at the interface (Arg-103) weakens the interface significantly, whereas effects are negligible when a hydrophilic (Ser-109) or a hydrophobic (Ile-305) amino acid is mutated instead. It has been suggested that clamp opening by the clamp loader takes advantage of spontaneous opening-closing fluctuations at the clamp's interface, but our time-resolved fluorescence and fluorescence correlation experiments rule out conformational fluctuations that lead to a significant fraction of open states.
[Mh] Termos MeSH primário: DNA Polimerase III/química
DNA Polimerase III/metabolismo
Escherichia coli/enzimologia
Multimerização Proteica
Eletricidade Estática
[Mh] Termos MeSH secundário: DNA Polimerase III/genética
Relação Dose-Resposta a Droga
Concentração de Íons de Hidrogênio
Mutação
Estabilidade Proteica/efeitos dos fármacos
Estrutura Quaternária de Proteína
Sais/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Salts); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (beta subunit, DNA polymerase III)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE


  7 / 2098 MEDLINE  
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[PMID]:28784720
[Au] Autor:Yu C; Gan H; Zhang Z
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
[Ti] Título:Both DNA Polymerases δ and ε Contact Active and Stalled Replication Forks Differently.
[So] Source:Mol Cell Biol;37(21), 2017 Nov 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Three DNA polymerases, polymerases α, δ, and ε (Pol α, Pol δ, and Pol ε), are responsible for eukaryotic genome duplication. When DNA replication stress is encountered, DNA synthesis stalls until the stress is ameliorated. However, it is not known whether there is a difference in the association of each polymerase with active and stalled replication forks. Here, we show that each DNA polymerase has a distinct pattern of association with active and stalled replication forks. Pol α is enriched at extending Okazaki fragments of active and stalled forks. In contrast, although Pol δ contacts the nascent lagging strands of active and stalled forks, it binds to only the matured (and not elongating) Okazaki fragments of stalled forks. Pol ε has greater contact with the nascent single-stranded DNA (ssDNA) of the leading strand on active forks than on stalled forks. We propose that the configuration of DNA polymerases at stalled forks facilitates the resumption of DNA synthesis after stress removal.
[Mh] Termos MeSH primário: DNA Polimerase III/metabolismo
DNA Polimerase II/metabolismo
DNA Fúngico/metabolismo
Saccharomyces cerevisiae/genética
[Mh] Termos MeSH secundário: DNA/metabolismo
Replicação do DNA
DNA de Cadeia Simples/metabolismo
Saccharomyces cerevisiae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (DNA, Single-Stranded); 0 (Okazaki fragments); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


  8 / 2098 MEDLINE  
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[PMID]:28781235
[Au] Autor:Guo X; Hum YF; Lehner K; Jinks-Robertson S
[Ad] Endereço:Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
[Ti] Título:Regulation of hetDNA Length during Mitotic Double-Strand Break Repair in Yeast.
[So] Source:Mol Cell;67(4):539-549.e4, 2017 Aug 17.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heteroduplex DNA (hetDNA) is a key molecular intermediate during the repair of mitotic double-strand breaks by homologous recombination, but its relationship to 5' end resection and/or 3' end extension is poorly understood. In the current study, we examined how perturbations in these processes affect the hetDNA profile associated with repair of a defined double-strand break (DSB) by the synthesis-dependent strand-annealing (SDSA) pathway. Loss of either the Exo1 or Sgs1 long-range resection pathway significantly shortened hetDNA, suggesting that these pathways normally collaborate during DSB repair. In addition, altering the processivity or proofreading activity of DNA polymerase δ shortened hetDNA length or reduced break-adjacent mismatch removal, respectively, demonstrating that this is the primary polymerase that extends both 3' ends. Data are most consistent with the extent of DNA synthesis from the invading end being the primary determinant of hetDNA length during SDSA.
[Mh] Termos MeSH primário: Quebras de DNA de Cadeia Dupla
Reparo do DNA
DNA Fúngico/metabolismo
Mitose
Ácidos Nucleicos Heteroduplexes/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: DNA Polimerase III/genética
DNA Polimerase III/metabolismo
DNA Fúngico/genética
Exodesoxirribonucleases/genética
Exodesoxirribonucleases/metabolismo
Genótipo
Mutação
Ácidos Nucleicos Heteroduplexes/genética
Fenótipo
Polimorfismo de Nucleotídeo Único
RecQ Helicases/genética
RecQ Helicases/metabolismo
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/crescimento & desenvolvimento
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (Nucleic Acid Heteroduplexes); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.7.- (DNA Polymerase III); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.11.1 (exodeoxyribonuclease I); EC 3.6.1.- (SGS1 protein, S cerevisiae); EC 3.6.4.12 (RecQ Helicases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE


  9 / 2098 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


  10 / 2098 MEDLINE  
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[PMID]:28656718
[Au] Autor:Pandey P; Verma V; Gautam G; Kumari N; Dhar SK; Gourinath S
[Ad] Endereço:School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
[Ti] Título:Targeting the ß-clamp in Helicobacter pylori with FDA-approved drugs reveals micromolar inhibition by diflunisal.
[So] Source:FEBS Lett;591(15):2311-2322, 2017 Aug.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The ß-clamp is the processivity-promoting factor for most of the enzymes in prokaryotic DNA replication; hence, it is a crucial drug target. In the present study, we investigated the ß-clamp from Helicobacter pylori, aiming to seek potential drug molecules against this gastric-cancer-causing bacterium. An in silico screening of Food and Drug Administration (FDA) approved drugs against the H. pylori ß-clamp, followed by its in vitro inhibition using a surface competition approach, yielded the drug diflunisal as a positive initial hit. Diflunisal inhibits the growth of H. pylori in the micromolar range. We determined the structure of diflunisal in complex with the ß-clamp to show that the drug binds at subsite I, which is a protein-protein interaction site. Successful identification of FDA-approved molecules against H. pylori may lead to better and faster drug development.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
DNA Polimerase III/antagonistas & inibidores
DNA Polimerase III/química
Diflunisal/farmacologia
Helicobacter pylori/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antibacterianos/química
Sítios de Ligação
Cristalografia por Raios X
DNA Ligases/metabolismo
DNA Polimerase III/metabolismo
Diflunisal/química
Aprovação de Drogas
Avaliação Pré-Clínica de Medicamentos/métodos
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Helicobacter pylori/enzimologia
Concentração Inibidora 50
Simulação de Acoplamento Molecular
Conformação Proteica
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Enzyme Inhibitors); 7C546U4DEN (Diflunisal); EC 2.7.7.- (DNA Polymerase III); EC 6.5.1.- (DNA Ligases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12734



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