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[PMID]:28465371
[Au] Autor:Castellucci E; He T; Goldstein DY; Halmos B; Chuy J
[Ad] Endereço:Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
[Ti] Título:DNA Polymerase É› Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity.
[So] Source:Oncologist;22(5):497-502, 2017 May.
[Is] ISSN:1549-490X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase É› have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in lead to impaired proofreading intrinsic to Pol É› during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol É› have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here. 2017;22:497-502 KEY POINTS: Clinicians should recognize that tumors with high tumor mutation burden and that are microsatellite stable may harbor a mutation, which is associated with an ultramutated phenotype.Work-up for deficiency should indeed become part of the routine molecular testing paradigm for patients with colorectal cancer.This subset of patients may benefit from clinical trials where the higher number of mutation-associated neoantigens and defect in DNA repair may be exploited therapeutically.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
DNA Polimerase II/genética
Instabilidade de Microssatélites
Proteínas de Ligação a Poli-ADP-Ribose/genética
Prognóstico
[Mh] Termos MeSH secundário: Neoplasias Colorretais/patologia
DNA Polimerase II/deficiência
Reparo do DNA/genética
Genótipo
Mutação em Linhagem Germinativa/genética
Seres Humanos
Masculino
Meia-Idade
Metástase Neoplásica
Fenótipo
Proteínas de Ligação a Poli-ADP-Ribose/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1634/theoncologist.2017-0034


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[PMID]:29275239
[Au] Autor:Singh J; Srivastva AK; Mandal P; Chandra S; Dubey D; Dwivedi A; Chopra D; Tripathi A; Ray RS
[Ad] Endereço:Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow,
[Ti] Título:Under ambient UVA exposure, pefloxacin exhibits both immunomodulatory and genotoxic effects via multiple mechanisms.
[So] Source:J Photochem Photobiol B;178:593-605, 2018 Jan.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Pefloxacin (PFLX) is an antibiotic, which shows broad spectrum antimicrobial activities. It is an important derivative of fluoroquinolones (FLQs) group. Ultraviolet radiation (200-400nm) causes major problem for living being which comes at the earth surface naturally through sunlight and increasing regularly due to ozone depletion. PFLX was photodegraded in 5h and forms photoproduct under UVA exposure. At the non photocytotoxic dose PFLX, shows reduced phagocytosis activity, NO (nitric oxide) production, large vacuole formation and down regulated IL-6, TNF-α and IL-1 in BALB/c macrophages at both genes and proteins levels. At higher doses (photocytotoxic doses), PFLX induced a concentration dependent decrease in cell viability of human keratinocyte cell line (HaCaT) and peritoneal macrophages of BALB/c mice. Our molecular docking suggests that PFLX binds only to the cleaved DNA in the DNA-human TOP2A complex. Topoisomerase assay confirmed that PFLX inhibits human topoisomerase by forming an adduct with DNA. Photosensitized PFLX also caused intracellular ROS mediated DNA damage and formation of micronuclei and cyclobutane pyrimidine dimers (CPDs). Increase intracellular ROS leads to apoptosis which was proved through lysosomal destabilization and reduced mitochondrial membrane potential (MMP). Our present study shows that ambient UVA exposure in the presence of PFLX caused immunomodulatory as well as photogenotoxic effects. Therefore, patients under PFLX drug treatment should avoid sunlight exposure, especially during peak hours for their photosafety.
[Mh] Termos MeSH primário: Dano ao DNA/efeitos dos fármacos
Pefloxacina/química
Fármacos Fotossensibilizantes/química
Raios Ultravioleta
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Apoptose/efeitos da radiação
Sítios de Ligação
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos da radiação
Células Cultivadas
DNA/química
DNA/metabolismo
Dano ao DNA/efeitos da radiação
DNA Topoisomerases Tipo II/química
DNA Topoisomerases Tipo II/metabolismo
Feminino
Seres Humanos
Interleucina-6/genética
Interleucina-6/metabolismo
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Macrófagos/efeitos da radiação
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos da radiação
Camundongos
Simulação de Acoplamento Molecular
Pefloxacina/toxicidade
Fármacos Fotossensibilizantes/toxicidade
Proteínas de Ligação a Poli-ADP-Ribose/química
Proteínas de Ligação a Poli-ADP-Ribose/metabolismo
Dímeros de Pirimidina/análise
Espécies Reativas de Oxigênio/metabolismo
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-6); 0 (Photosensitizing Agents); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Pyrimidine Dimers); 0 (Reactive Oxygen Species); 0 (Tumor Necrosis Factor-alpha); 2H52Z9F2Q5 (Pefloxacin); 9007-49-2 (DNA); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2A protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


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[PMID]:29320758
[Au] Autor:Voutsadakis IA
[Ad] Endereço:Division of Medical Oncology, Department of Internal Medicine, Sault Area Hospital, Sault Ste Marie, Ontario, Canada; Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada. Electronic address: ivoutsadakis@nosm.ca.
[Ti] Título:Polymerase epsilon mutations and concomitant ß2-microglobulin mutations in cancer.
[So] Source:Gene;647:31-38, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system. This paper investigates the mutagenic effect of different POLE mutations in various cancers, in published genomic studies and the effect that these POLE mutations have in selecting for mutations of the ß2 microglobulin (B2M) gene involved in antigen presentation.
[Mh] Termos MeSH primário: DNA Polimerase II/genética
Globulinas/genética
Mutação/genética
Neoplasias/genética
Proteínas de Ligação a Poli-ADP-Ribose/genética
[Mh] Termos MeSH secundário: Replicação do DNA/genética
Exodesoxirribonucleases/genética
Seres Humanos
Instabilidade de Microssatélites
Mutagênese/genética
Taxa de Mutação
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Globulins); 0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human); EC 3.1.- (Exodeoxyribonucleases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:28977631
[Au] Autor:Wang YR; Chen SF; Wu CC; Liao YW; Lin TS; Liu KT; Chen YS; Li TK; Chien TC; Chan NL
[Ad] Endereço:Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
[Ti] Título:Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.
[So] Source:Nucleic Acids Res;45(18):10861-10871, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2ß, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2ß revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2ß, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2ß more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2ß are practically irreversible. Crystallographic analyses of hTop2ß complexed with DNA and etoplatin-N2ß demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.
[Mh] Termos MeSH primário: Antineoplásicos/química
Quebras de DNA
Proteínas de Ligação a DNA/antagonistas & inibidores
Compostos Organoplatínicos/química
Podofilotoxina/análogos & derivados
Inibidores da Topoisomerase II/química
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/química
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
DNA/química
DNA Topoisomerases Tipo II/química
Proteínas de Ligação a DNA/química
Células HL-60
Seres Humanos
Metionina/química
Compostos Organoplatínicos/farmacologia
Podofilotoxina/química
Podofilotoxina/farmacologia
Proteínas de Ligação a Poli-ADP-Ribose
Conformação Proteica
Inibidores da Topoisomerase II/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Organoplatinum Compounds); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Topoisomerase II Inhibitors); 0 (etoplatin-N2beta); 9007-49-2 (DNA); AE28F7PNPL (Methionine); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2A protein, human); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx742


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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


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[PMID]:28815403
[Au] Autor:Zhou Z; Liu S; Zhang M; Zhou R; Liu J; Chang Y; Zhao Q
[Ad] Endereço:Department of Gastroenterology, Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei Province, People's Republic of China.
[Ti] Título:Overexpression of Topoisomerase 2-Alpha Confers a Poor Prognosis in Pancreatic Adenocarcinoma Identified by Co-Expression Analysis.
[So] Source:Dig Dis Sci;62(10):2790-2800, 2017 Oct.
[Is] ISSN:1573-2568
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of human cancer-related death in the developed countries. Its progression and prognosis are influenced by a complex network of gene interactions. AIMS: The purpose of this study is to explore key genes associated with pancreatic ductal adenocarcinoma and to predict the possible mechanisms. METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with the progression of PDAC. RESULTS: In the significant module (R  = 0.30), a total of 20 network hub genes were identified, 6 of which were also hub nodes in the protein-protein interaction network of the module genes. In validation, TOP2A has a higher correlation than other hub genes. Also, in the test set (n = 118), TOP2A was more highly expressed in PDAC than normal pancreas samples (P < 0.001). What is more, gene set enrichment analysis demonstrated that eight gene sets (n = 118), "nucleotide excision repair," "P53 signaling pathway," "proteasome," "mismatch repair," "homologous recombination," "DNA replication," "cell cycle," and "base excision repair," were enriched (FDR < 0.05). In gene ontology analysis, TOP2A in the enriched set was associated with cell cycle and cell division. Furthermore, survival analysis indicated that higher expression of TOP2A resulted in the lower overall survival time as well as disease-free survival time. CONCLUSION: TOP2A was identified in association with the progression and prognosis of PDAC probably by regulating cell cycle and p53 signaling pathway.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/genética
Carcinoma Ductal Pancreático/genética
DNA Topoisomerases Tipo II/genética
Proteínas de Ligação a DNA/genética
Redes Reguladoras de Genes
Neoplasias Pancreáticas/genética
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/metabolismo
Carcinoma Ductal Pancreático/enzimologia
Carcinoma Ductal Pancreático/patologia
Ciclo Celular/genética
Biologia Computacional
DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Bases de Dados Genéticas
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Neoplasias Pancreáticas/enzimologia
Neoplasias Pancreáticas/patologia
Proteínas de Ligação a Poli-ADP-Ribose
Prognóstico
Mapas de Interação de Proteínas
Transdução de Sinais
Biologia de Sistemas
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (DNA-Binding Proteins); 0 (Poly-ADP-Ribose Binding Proteins); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2A protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1007/s10620-017-4718-4


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[PMID]:28813519
[Au] Autor:Amirnasr A; Verdijk RM; van Kuijk PF; Taal W; Sleijfer S; Wiemer EAC
[Ad] Endereço:Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
[Ti] Título:Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors.
[So] Source:PLoS One;12(8):e0183155, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A). Recent molecular studies using murine models and cell lines identified the bromodomain containing protein 4 (BRD4) and enhancer of zeste homolog 2 (EZH2) as novel targets for MPNST treatment. We investigated the expression and potential use of BRD4, EZH2 and TOP2A as therapeutic targets in human NF1-derived MPNSTs. The transcript levels of BRD4, EZH2 and TOP2A were determined in paired formalin-fixed paraffin-embedded (FFPE) neurofibroma/MPNST samples derived from the same NF1 patient and in a set of plexiform neurofibromas, atypical neurofibromas and MPNST. We further examined the effect on cell viability of genetic or pharmacological inhibition of BRD4, EZH2 and TOP2A in an MPNST cell line panel. Our results indicated that in MPNST samples BRD4 mRNA levels were not upregulated and that MPNST cell lines were relatively insensitive to the bromodomain inhibitor JQ1. We corroborated that EZH2 mRNA expression is increased in MPNST but failed to confirm its reported pivotal role in MPNST pathogenesis as EZH2 knockdown by siRNA did not interfere with cellular proliferation and viability. Finally, the relation between TOP2A levels and sensitivity for doxorubicin was examined, confirming reports that TOP2A mRNA levels were overexpressed in MPNST and showing that MPNST cell lines exhibited relatively high TOP2A protein levels and sensitivity to doxorubicin. We tentatively conclude that the potential for effective therapeutic intervention in MPNST by targeting BRD4, EZH2 and TOP2A individually, may be limited. Clinical studies are necessary to ultimately prove the relevance of BRD4 and EZH2 inhibition as novel therapeutic strategies for MPNST.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/genética
DNA Topoisomerases Tipo II/genética
Proteínas de Ligação a DNA/genética
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Regulação Neoplásica da Expressão Gênica
Neoplasias da Bainha Neural/fisiopatologia
Neurofibroma/fisiopatologia
Proteínas Nucleares/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Antibióticos Antineoplásicos/farmacologia
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Criança
Pré-Escolar
Proteínas de Ligação a DNA/antagonistas & inibidores
Doxorrubicina/farmacologia
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Técnicas In Vitro
Masculino
Meia-Idade
Neoplasias da Bainha Neural/genética
Neurofibroma/genética
Proteínas Nucleares/antagonistas & inibidores
Proteínas de Ligação a Poli-ADP-Ribose
Fatores de Transcrição/antagonistas & inibidores
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Antigens, Neoplasm); 0 (BRD4 protein, human); 0 (DNA-Binding Proteins); 0 (Nuclear Proteins); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Transcription Factors); 80168379AG (Doxorubicin); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2A 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:170817
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183155


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[PMID]:28805995
[Au] Autor:Andrianova MA; Chetan GK; Sibin MK; Mckee T; Merkler D; Narasinga RK; Ribaux P; Blouin JL; Makrythanasis P; Seplyarskiy VB; Antonarakis SE; Nikolaev SI
[Ad] Endereço:Institute of Information Transmission Problems, Moscow, Russia.
[Ti] Título:Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.
[So] Source:J Pathol;243(3):331-341, 2017 Nov.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/genética
Reparo de Erro de Pareamento de DNA/genética
DNA Polimerase II/genética
Predisposição Genética para Doença
Mutação em Linhagem Germinativa/genética
Endonuclease PMS2 de Reparo de Erro de Pareamento/genética
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/patologia
DNA/genética
Feminino
Seres Humanos
Masculino
Proteínas de Ligação a Poli-ADP-Ribose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Poly-ADP-Ribose Binding Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human); EC 3.6.1.- (PMS2 protein, human); EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1002/path.4957


  9 / 1482 MEDLINE  
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[PMID]:28755480
[Au] Autor:Galan A; Lozano G; Piñeiro D; Martinez-Salas E
[Ad] Endereço:Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid, Spain.
[Ti] Título:G3BP1 interacts directly with the FMDV IRES and negatively regulates translation.
[So] Source:FEBS J;284(19):3202-3217, 2017 Oct.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:RNA-protein interactions play a pivotal role in the function of picornavirus internal ribosome entry site (IRES) elements. Here we analysed the impact of Ras GTPase SH3 domain binding protein 1 (G3BP1) in the IRES activity of foot-and-mouth disease virus (FMDV). We found that G3BP1 interacts directly with three distinct sequences of the IRES element using RNA electrophoretic mobility-shift assays. Analysis of the interaction with domain 5 indicated that the G3BP1 binding-site is placed at the single-stranded region although it allows large sequence heterogeneity and the hairpin located upstream of this region enhances retarded complex formation. In addition, G3BP1 interacts directly with the polypyrimidine tract-binding protein and the translation initiation factor 4B (eIF4B) through the C-terminal region. Moreover, G3BP1 is cleaved during FMDV infection yielding two fragments, Ct-G3BP1 and Nt-G3BP1. Both fragments inhibit cap- and IRES-dependent translation, but the Ct-G3BP1 fragment shows a stronger effect on IRES-dependent translation. Assembly of complexes with G3BP1 results in a significantly reduced local flexibility of the IRES element, consistent with the negative effect of this protein. Our results highlight the IRES-binding capacity of G3BP1 and illustrate its function as a translation inhibitor.
[Mh] Termos MeSH primário: Proteínas de Transporte/química
Fatores de Iniciação em Eucariotos/genética
Vírus da Febre Aftosa/química
Sítios Internos de Entrada Ribossomal
Biossíntese de Proteínas
RNA Viral/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Clonagem Molecular
DNA Helicases
Escherichia coli/genética
Escherichia coli/metabolismo
Fatores de Iniciação em Eucariotos/química
Fatores de Iniciação em Eucariotos/metabolismo
Vírus da Febre Aftosa/genética
Vírus da Febre Aftosa/metabolismo
Expressão Gênica
Células HEK293
Seres Humanos
Cinética
Conformação de Ácido Nucleico
Proteínas de Ligação a Poli-ADP-Ribose
Ligação Proteica
RNA Helicases
Proteínas com Motivo de Reconhecimento de RNA
RNA Viral/genética
RNA Viral/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Ribossomos/genética
Ribossomos/metabolismo
Técnica de Seleção de Aptâmeros
Alinhamento de Sequência
Homologia de Sequência do Ácido Nucleico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Eukaryotic Initiation Factors); 0 (Internal Ribosome Entry Sites); 0 (Poly-ADP-Ribose Binding Proteins); 0 (RNA Recognition Motif Proteins); 0 (RNA, Viral); 0 (Recombinant Proteins); 0 (eIF-4B); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (G3BP1 protein, human); EC 3.6.4.13 (RNA Helicases)
[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:170730
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14184


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[PMID]:28735753
[Au] Autor:Canela A; Maman Y; Jung S; Wong N; Callen E; Day A; Kieffer-Kwon KR; Pekowska A; Zhang H; Rao SSP; Huang SC; Mckinnon PJ; Aplan PD; Pommier Y; Aiden EL; Casellas R; Nussenzweig A
[Ad] Endereço:Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
[Ti] Título:Genome Organization Drives Chromosome Fragility.
[So] Source:Cell;170(3):507-521.e18, 2017 Jul 27.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.
[Mh] Termos MeSH primário: Fragilidade Cromossômica
Quebras de DNA de Cadeia Dupla
Neoplasias/genética
[Mh] Termos MeSH secundário: Animais
Linfócitos B/metabolismo
Fator de Ligação a CCCTC
Linhagem Celular Tumoral
DNA Topoisomerases Tipo II/metabolismo
Proteínas de Ligação a DNA/metabolismo
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Proteínas de Ligação a Poli-ADP-Ribose
Proteínas Repressoras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCCTC-Binding Factor); 0 (CTCF protein, human); 0 (Ctcf protein, mouse); 0 (DNA-Binding Proteins); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Repressor Proteins); EC 5.99.1.3 (DNA Topoisomerases, Type II); EC 5.99.1.3 (TOP2B protein, human); EC 5.99.1.3 (Top2b protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE



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