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[PMID]:29277765
[Au] Autor:Yang G; Qiu J; Wang D; Tao Y; Song Y; Wang H; Tang J; Wang X; Sun YU; Yang Z; Hoffman RM
[Ad] Endereço:Hangzhou Third Hospital, Hangzhou, P.R. China.
[Ti] Título:Traditional Chinese Medicine Curcumin Sensitizes Human Colon Cancer to Radiation by Altering the Expression of DNA Repair-related Genes.
[So] Source:Anticancer Res;38(1):131-136, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The aim of the present study was to investigate the radio-sensitizing efficacy of curcumin, a traditional Chinese medicine (TCM) on colon cancer cells in vitro and in vivo. MATERIALS AND METHODS: Human colon cancer HT-29 cells were treated with curcumin (2.5 µM), irradiation (10 Gy) and the combination of irradiation and curcumin. Cell proliferation was assessed using the MTT assay. Apoptotic cells were detected by Annexin V-PE/7-AAD analysis. PCR was performed to determine differential-expression profiling of 95 DNA-repair genes in irradiated cells and cells treated with both irradiation and curcumin. Differentially-expressed genes were confirmed by Western blotting. In vivo radio-sensitizing efficacy of curcumin was assessed in a xenograft mouse model of HT-29 colon cancer. Curcumin was administrated daily by intraperitoneal injection at 20 mg/kg/dose. Mice received irradiation (10 Gy) twice weekly. Apoptosis of the cancer cells following treatment was determined by TUNEL staining. RESULTS: Irradiation induced proliferation inhibition and apoptosis of HT-29 cells in vitro. Concurrent curcumin treatment sensitized the HT-29 tumor to irradiation (p<0.01). DNA repair-related genes CCNH and XRCC5 were upregulated and LIG4 and PNKP downregulated by the combination of curcumin and irradiation compared with irradiation alone (p<0.05). Combined treatment of curcumin and irradiation resulted in a significantly greater tumor-growth inhibition and apoptosis compared to irradiation treatment alone (p<0.01). CONCLUSION: Curcumin sensitizes human colon cancer in vitro and in vivo to radiation. Downregulation of LIG4 and PNKP and upregulation of XRCC5 and CCNH DNA-repair-related genes were involved in the radio-sensitizing efficacy of curcumin in colon cancer.
[Mh] Termos MeSH primário: Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/radioterapia
Curcumina/farmacologia
Curcumina/uso terapêutico
Radiossensibilizantes/farmacologia
Radiossensibilizantes/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Apoptose/efeitos da radiação
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/efeitos da radiação
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Ciclina H/genética
Ciclina H/metabolismo
DNA Ligase Dependente de ATP/genética
DNA Ligase Dependente de ATP/metabolismo
Reparo do DNA/genética
Enzimas Reparadoras do DNA/genética
Enzimas Reparadoras do DNA/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Células HT29
Seres Humanos
Autoantígeno Ku/genética
Autoantígeno Ku/metabolismo
Medicina Tradicional Chinesa
Camundongos Endogâmicos BALB C
Camundongos Nus
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Carga Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCNH protein, human); 0 (Cyclin H); 0 (LIG4 protein, human); 0 (Radiation-Sensitizing Agents); EC 2.7.1.- (PNKP protein, human); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 3.6.4.12 (XRCC5 protein, human); EC 4.2.99.- (Ku Autoantigen); EC 6.5.1.- (DNA Repair Enzymes); EC 6.5.1.1 (DNA Ligase ATP); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status: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


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[PMID]:28803780
[Au] Autor:Ferry L; Fournier A; Tsusaka T; Adelmant G; Shimazu T; Matano S; Kirsh O; Amouroux R; Dohmae N; Suzuki T; Filion GJ; Deng W; de Dieuleveult M; Fritsch L; Kudithipudi S; Jeltsch A; Leonhardt H; Hajkova P; Marto JA; Arita K; Shinkai Y; Defossez PA
[Ad] Endereço:Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
[Ti] Título:Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.
[So] Source:Mol Cell;67(4):550-565.e5, 2017 Aug 17.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance.
[Mh] Termos MeSH primário: Proteínas Estimuladoras de Ligação a CCAAT/metabolismo
DNA Ligase Dependente de ATP/metabolismo
Metilação de DNA
Replicação do DNA
DNA/biossíntese
Epigênese Genética
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Animais
Proteínas Estimuladoras de Ligação a CCAAT/química
Proteínas Estimuladoras de Ligação a CCAAT/genética
DNA/genética
DNA Ligase Dependente de ATP/química
DNA Ligase Dependente de ATP/genética
Células-Tronco Embrionárias/enzimologia
Células HEK293
Células HeLa
Antígenos de Histocompatibilidade/química
Antígenos de Histocompatibilidade/genética
Histona-Lisina N-Metiltransferase/química
Histona-Lisina N-Metiltransferase/genética
Histonas/metabolismo
Seres Humanos
Lisina
Metilação
Camundongos
Modelos Moleculares
Mimetismo Molecular
Mutação
Ligação Proteica
Conformação Proteica
Relação Estrutura-Atividade
Transfecção
Domínio Tudor
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Proteins); 0 (Histocompatibility Antigens); 0 (Histones); 0 (LIG1 protein, human); 0 (Lig1 protein, mouse); 0 (UHRF1 protein, human); 9007-49-2 (DNA); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 6.5.1.1 (DNA Ligase ATP); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28751376
[Au] Autor:McNally JR; O'Brien PJ
[Ad] Endereço:From the Department of Biological Chemistry, Michigan Medicine, University of Michigan, Ann Arbor, Michigan 48109.
[Ti] Título:Kinetic analyses of single-stranded break repair by human DNA ligase III isoforms reveal biochemical differences from DNA ligase I.
[So] Source:J Biol Chem;292(38):15870-15879, 2017 Sep 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Humans have three genes encoding DNA ligases with conserved structural features and activities, but they also have notable differences. The gene encodes a ubiquitous isoform in all tissues (LIG3α) and a germ line-specific splicing isoform (LIG3ß) that differs in the C-terminal domain. Both isoforms are found in the nucleus and the mitochondria. Here, we determined the kinetics and thermodynamics of single-stranded break ligation by LIG3α and LIG3ß and compared this framework to that of LIG1, the nuclear replicative ligase. The kinetic parameters of the LIG3 isoforms are nearly identical under all tested conditions, indicating that the BRCA1 C terminal (BRCT) domain specific to LIG3α does not alter ligation kinetics. Although LIG3 is only 22% identical to LIG1 across their conserved domains, the two enzymes had very similar maximal ligation rates. Comparison of the rate and equilibrium constants for LIG3 and LIG1 nevertheless revealed important differences. The LIG3 isoforms were seven times more efficient than LIG1 at ligating nicked DNA under optimal conditions, mainly because of their lower value for the DNA substrate. This could explain why LIG3 is less prone to abortive ligation than LIG1. Surprisingly, the affinity of LIG3 for Mg was ten times weaker than that of LIG1, suggesting that Mg availability regulates DNA ligation , because Mg levels are higher in the mitochondria than in the nucleus. The biochemical differences between the LIG3 isoforms and LIG1 identified here will guide the understanding of both unique and overlapping biological roles of these critical enzymes.
[Mh] Termos MeSH primário: Quebras de DNA de Cadeia Simples
DNA Ligase Dependente de ATP/metabolismo
Reparo do DNA
[Mh] Termos MeSH secundário: Monofosfato de Adenosina/metabolismo
Sequência Conservada
DNA Ligase Dependente de ATP/química
Relação Dose-Resposta a Droga
Estabilidade Enzimática
Seres Humanos
Isoenzimas/química
Isoenzimas/metabolismo
Cinética
Magnésio/farmacologia
Modelos Moleculares
Conformação Proteica
Processamento de Proteína Pós-Traducional
Especificidade por Substrato
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 415SHH325A (Adenosine Monophosphate); EC 6.5.1.1 (DNA Ligase ATP); I38ZP9992A (Magnesium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804625


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[PMID]:28696258
[Au] Autor:Gerodimos CA; Chang HHY; Watanabe G; Lieber MR
[Ad] Endereço:From the Departments of Pathology, Biochemistry & Molecular Biology, and Molecular Microbiology & Immunology and the Department of Biological Sciences, Section of Molecular & Computational Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medic
[Ti] Título:Effects of DNA end configuration on XRCC4-DNA ligase IV and its stimulation of Artemis activity.
[So] Source:J Biol Chem;292(34):13914-13924, 2017 Aug 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In humans, nonhomologous DNA end-joining (NHEJ) is the major pathway by which DNA double-strand breaks are repaired. Recognition of each broken DNA end by the DNA repair protein Ku is the first step in NHEJ, followed by the iterative binding of nucleases, DNA polymerases, and the XRCC4-DNA ligase IV (X4-LIV) complex in an order influenced by the configuration of the two DNA ends at the break site. The endonuclease Artemis improves joining efficiency by functioning in a complex with DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) that carries out endonucleolytic cleavage of 5' and 3' overhangs. Previously, we observed that X4-LIV alone can stimulate Artemis activity on 3' overhangs, but this DNA-PKcs-independent endonuclease activity of Artemis awaited confirmation. Here, using nuclease and ligation assays, we find that stimulation of Artemis nuclease activity by X4-LIV and the efficiency of blunt-end ligation are determined by structural configurations at the DNA end. Specifically, X4-LIV stimulated Artemis to cut near the end of 3' overhangs without the involvement of other NHEJ proteins. Of note, this ligase complex is not able to stimulate Artemis activity at hairpins or at 5' overhangs. We also found that X4-LIV and DNA-PKcs interfere with one another with respect to stimulating Artemis activity at 3' overhangs, favoring the view that these NHEJ proteins are sequentially rather than concurrently recruited to DNA ends. These data suggest specific functional and positional relationships among these components that explain genetic and molecular features of NHEJ and V(D)J recombination within cells.
[Mh] Termos MeSH primário: DNA Ligase Dependente de ATP/metabolismo
Proteínas de Ligação a DNA/metabolismo
Endonucleases/metabolismo
Modelos Moleculares
Reparo de DNA por Recombinação
Recombinação V(D)J
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
DNA/química
DNA/metabolismo
Quebras de DNA de Cadeia Dupla
Reparo do DNA por Junção de Extremidades
DNA Ligase Dependente de ATP/química
DNA Ligase Dependente de ATP/genética
Proteína Quinase Ativada por DNA/química
Proteína Quinase Ativada por DNA/metabolismo
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Endonucleases/química
Células HeLa
Seres Humanos
Cinética
Mariposas
Proteínas Nucleares/química
Proteínas Nucleares/metabolismo
Conformação de Ácido Nucleico
Multimerização Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Células Sf9
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (LIG4 protein, human); 0 (Nuclear Proteins); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (XRCC4 protein, human); 9007-49-2 (DNA); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.1 (PRKDC protein, human); EC 3.1.- (Endonucleases); EC 3.1.- (artemis nuclease, human); EC 6.5.1.1 (DNA Ligase ATP)
[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:170712
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.798850


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[PMID]:28554891
[Au] Autor:Ribeiro HL; Maia ARS; de Oliveira RTG; Costa MB; Farias IR; de Paula Borges D; de Sousa JC; Magalhães SMM; Pinheiro RF
[Ad] Endereço:Cancer Cytogenomic Laboratory, Center for Research and Drug Development (NPDM), Federal University of Ceara, Fortaleza, Ceara, Brazil.
[Ti] Título:DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome.
[So] Source:J Clin Pathol;70(11):970-980, 2017 Nov.
[Is] ISSN:1472-4146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To evaluate the expression of genes related to nuclear excision ( , and ), homologous recombination and non-homologous end-joining ( , , and ) repair mechanisms, using quantitative PCR methodologies, and it relation with bone marrow cellularity in myelodysplastic syndrome (MDS). METHODS AND RESULTS: A total of 51 adult de novo patients with MDS (3 refractory anaemia (RA), 11 refractory anaemia with ringed sideroblasts (RARS), 28 refractory cytopenia with multilineage dysplasia (RCMD), 3 refractory anaemia with excess blasts type I (RAEB-I), 5 refractory anaemia with excess blasts type II (RAEB-II), and 1 chronic myelomonocytic leukaemia (CMML) were evaluated. For karyotype, 16.2% patients were defined as very low prognosis, 59.5% low risk, 8.1% intermediate risk, 5.4% high risk and 10.8% very high risk. For bone marrow cellularity, 17.6%, 17.6% and 64.7% presented as hypocellular, normocellular and hypercellular, respectively. Patients with hypocellular MDS had significantly decreased expression of (p=0.000) (p=0.014), (p=0.003) (p=0.004) and (p=0.000) than those with normocellular/hypercellular bone marrow, whereas (p=0.049) and (p=0.000) genes were increased. In patients with hypoplastic MDS, a low expression of (p=0.0268), (p=0.0199) and (p=0.0493) was significantly associated with the presence of chromosomal abnormalities. We detected positive correlations between and (r=0.416; p=0.007), and (r=0.472; p=0.001), and (r=0.333; p=0.026), and (r=0.334; p=0.025), and (r=0.377; p=0.008), and (r=0.287; p=0.046), and (r=0.371; p=0.007) and and genes (r=0.895; p=0.0000). We also found among all patients evaluated that correlation with occurred most often. CONCLUSIONS: These correlations demonstrate the important intrinsic relations between single and double DNA strand breaks genes in MDS, emphasising that these genes are related to MDS pathogenesis.
[Mh] Termos MeSH primário: Células da Medula Óssea/patologia
Enzimas Reparadoras do DNA/genética
Reparo do DNA
Síndromes Mielodisplásicas/genética
Síndromes Mielodisplásicas/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Proteínas Mutadas de Ataxia Telangiectasia/genética
Proteína BRCA1/genética
Proteína BRCA2/genética
Biópsia
Exame de Medula Óssea
Quebras de DNA de Cadeia Dupla
Quebras de DNA de Cadeia Simples
DNA Ligase Dependente de ATP/genética
Proteínas de Ligação a DNA/genética
Feminino
Regulação Enzimológica da Expressão Gênica
Marcadores Genéticos
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Síndromes Mielodisplásicas/mortalidade
Valor Preditivo dos Testes
Reação em Cadeia da Polimerase em Tempo Real
Fatores de Transcrição/genética
Proteína de Xeroderma Pigmentoso Grupo A/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (DNA-Binding Proteins); 0 (ERCC8 protein, human); 0 (Genetic Markers); 0 (LIG4 protein, human); 0 (Transcription Factors); 0 (XPA protein, human); 0 (Xeroderma Pigmentosum Group A Protein); 156533-34-5 (XPC protein, human); EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 6.5.1.- (DNA Repair Enzymes); EC 6.5.1.1 (DNA Ligase ATP)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE
[do] DOI:10.1136/jclinpath-2016-204269


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[PMID]:28283070
[Au] Autor:Allen SE; Hug I; Pabian S; Rzeszutek I; Hoehener C; Nowacki M
[Ad] Endereço:Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland.
[Ti] Título:Circular Concatemers of Ultra-Short DNA Segments Produce Regulatory RNAs.
[So] Source:Cell;168(6):990-999.e7, 2017 Mar 09.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the ciliated protozoan Paramecium tetraurelia, Piwi-associated small RNAs are generated upon the elimination of tens of thousands of short transposon-derived DNA segments as part of development. These RNAs then target complementary DNA for elimination in a positive feedback process, contributing to germline defense and genome stability. In this work, we investigate the formation of these RNAs, which we show to be transcribed directly from the short (length mode 27 bp) excised DNA segments. Our data support a mechanism whereby the concatenation and circularization of excised DNA segments provides a template for RNA production. This process allows the generation of a double-stranded RNA for Dicer-like protein cleavage to give rise to a population of small regulatory RNAs that precisely match the excised DNA sequences. VIDEO ABSTRACT.
[Mh] Termos MeSH primário: DNA Concatenado
Paramecium tetraurellia/genética
[Mh] Termos MeSH secundário: Núcleo Celular/metabolismo
DNA Ligase Dependente de ATP/metabolismo
Elementos de DNA Transponíveis
Exodesoxirribonucleases/metabolismo
Paramecium tetraurellia/citologia
Paramecium tetraurellia/metabolismo
RNA/genética
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA Transposable Elements); 0 (DNA, Concatenated); 63231-63-0 (RNA); EC 3.1.- (Exodeoxyribonucleases); EC 6.5.1.1 (DNA Ligase ATP)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE


  8 / 841 MEDLINE  
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[PMID]:28082683
[Au] Autor:Niewolik D; Peter I; Butscher C; Schwarz K
[Ad] Endereço:From the Institute for Transfusion Medicine, University of Ulm and doris.niewolik@uni-ulm.de.
[Ti] Título:Autoinhibition of the Nuclease ARTEMIS Is Mediated by a Physical Interaction between Its Catalytic and C-terminal Domains.
[So] Source:J Biol Chem;292(8):3351-3365, 2017 Feb 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The nuclease ARTEMIS is essential for the development of B and T lymphocytes. It is required for opening DNA hairpins generated during antigen receptor gene assembly from variable (V), diversity (D), and joining (J) subgenic elements (V(D)J recombination). As a member of the non-homologous end-joining pathway, it is also involved in repairing a subset of pathological DNA double strand breaks. Loss of ARTEMIS function therefore results in radiosensitive severe combined immunodeficiency (RS-SCID). The hairpin opening activity is dependent on the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which can bind to and phosphorylate ARTEMIS. The ARTEMIS C terminus is dispensable for cellular V(D)J recombination and nuclease assays with C-terminally truncated ARTEMIS showing DNA-PKcs-independent hairpin opening activity. Therefore, it has been postulated that ARTEMIS is regulated via autoinhibition by its C terminus. To obtain evidence for the autoinhibition model, we performed co-immunoprecipitation experiments with combinations of ARTEMIS mutants. We show that an N-terminal fragment comprising the catalytic domain can interact both with itself and with a C-terminal fragment. Amino acid exchanges N456A+S457A+E458Q in the C terminus of full-length ARTEMIS resulted in unmasking of the N terminus and in increased ARTEMIS activity in cellular V(D)J recombination assays. Mutations in ARTEMIS-deficient patients impaired the interaction with the C terminus and also affected protein stability. The interaction between the N- and C-terminal domains was not DNA-PKcs-dependent, and phosphomimetic mutations in the C-terminal domain did not result in unmasking of the catalytic domain. Our experiments provide strong evidence that a physical interaction between the C-terminal and catalytic domains mediates ARTEMIS autoinhibition.
[Mh] Termos MeSH primário: Proteínas Nucleares/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
Células Cultivadas
DNA Ligase Dependente de ATP/metabolismo
Endonucleases
Fibroblastos/metabolismo
Células HEK293
Seres Humanos
Proteínas Nucleares/química
Proteínas Nucleares/genética
Mutação Puntual
Recombinação V(D)J
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nuclear Proteins); EC 3.1.- (DCLRE1C protein, human); EC 3.1.- (Endonucleases); EC 6.5.1.1 (DNA Ligase ATP)
[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:170114
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.770461


  9 / 841 MEDLINE  
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[PMID]:27312791
[Au] Autor:Pandey M; Kumar S; Goldsmith G; Srivastava M; Elango S; Shameem M; Bannerjee D; Choudhary B; Karki SS; Raghavan SC
[Ad] Endereço:Department of Biochemistry, Indian Institute of Science, Bangalore, India.
[Ti] Título:Identification and characterization of novel ligase I inhibitors.
[So] Source:Mol Carcinog;56(2):550-566, 2017 Feb.
[Is] ISSN:1098-2744
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: DNA Ligase Dependente de ATP/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Animais
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
DNA Ligase Dependente de ATP/química
DNA Ligase Dependente de ATP/metabolismo
Replicação do DNA/efeitos dos fármacos
Desenho de Drogas
Células HEK293
Seres Humanos
Masculino
Simulação de Acoplamento Molecular
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Small Molecule Libraries); EC 6.5.1.1 (DNA Ligase ATP)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160618
[St] Status:MEDLINE
[do] DOI:10.1002/mc.22516


  10 / 841 MEDLINE  
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[PMID]:27875301
[Au] Autor:Hammel M; Yu Y; Radhakrishnan SK; Chokshi C; Tsai MS; Matsumoto Y; Kuzdovich M; Remesh SG; Fang S; Tomkinson AE; Lees-Miller SP; Tainer JA
[Ad] Endereço:From the Molecular Biophysics & Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California 94720, mhammel@lbl.gov.
[Ti] Título:An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex.
[So] Source:J Biol Chem;291(53):26987-27006, 2016 12 30.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). Yet, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic. Here, small angle X-ray scattering (SAXS) and mutational analyses show APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcs (DNA-PK), and X4L4 within an extended flexible NHEJ core complex. X4L4 assembles with Ku heterodimers linked to DNA-PKcs via flexible Ku80 C-terminal regions (Ku80CTR) in a complex stabilized through APLF interactions with Ku, DNA-PK, and X4L4. Collective results unveil the solution architecture of the six-protein complex and suggest cooperative assembly of an extended flexible NHEJ core complex that supports APLF accessibility while possibly providing flexible attachment of the core complex to chromatin. The resulting dynamic tethering furthermore, provides geometric access of L4 catalytic domains to the DNA ends during ligation and of DNA-PKcs for targeted phosphorylation of other NHEJ proteins as well as trans-phosphorylation of DNA-PKcs on the opposing DSB without disrupting the core ligation complex. Overall the results shed light on evolutionary conservation of Ku, X4, and L4 activities, while explaining the observation that Ku80CTR and DNA-PKcs only occur in a subset of higher eukaryotes.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades/genética
DNA Ligase Dependente de ATP/metabolismo
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo
Proteína Quinase Ativada por DNA/metabolismo
Proteínas de Ligação a DNA/metabolismo
Autoantígeno Ku/metabolismo
Proteínas Nucleares/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Reagentes para Ligações Cruzadas
Quebras de DNA de Cadeia Dupla
DNA Ligase Dependente de ATP/química
DNA Ligase Dependente de ATP/genética
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética
Proteína Quinase Ativada por DNA/química
Proteína Quinase Ativada por DNA/genética
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Células HeLa
Seres Humanos
Imunoprecipitação
Autoantígeno Ku/química
Autoantígeno Ku/genética
Modelos Moleculares
Proteínas Nucleares/química
Proteínas Nucleares/genética
Fosforilação
Proteínas de Ligação a Poli-ADP-Ribose
Ligação Proteica
Conformação Proteica
Espalhamento a Baixo Ângulo
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cross-Linking Reagents); 0 (DNA-Binding Proteins); 0 (LIG4 protein, human); 0 (Nuclear Proteins); 0 (Poly-ADP-Ribose Binding Proteins); 0 (XRCC4 protein, human); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.1 (PRKDC protein, human); EC 3.6.4.12 (XRCC5 protein, human); EC 4.2.99.- (Ku Autoantigen); EC 4.2.99.18 (APLF protein, human); EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase); EC 6.5.1.1 (DNA Ligase ATP)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.751867



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