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  1 / 2318 MEDLINE  
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[PMID]:28459532
[Au] Autor:Paul R; Banerjee S; Greenberg MM
[Ad] Endereço:Department of Chemistry, Johns Hopkins University , 3400 N. Charles St., Baltimore, Maryland 21218, United States.
[Ti] Título:Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells.
[So] Source:ACS Chem Biol;12(6):1576-1583, 2017 06 16.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA repair is vital to maintaining genome integrity but thwarts the effects of cytotoxic agents that target nucleic acids. Consequently, repair enzymes are potential targets for molecules that modulate cell function and anticancer therapeutics. DNA polymerase ß (Pol ß) is an attractive target because it plays a key role in base excision repair (BER), a primary pathway that repairs the effects of many DNA damaging agents. We previously identified an irreversible inhibitor of Pol ß whose design was based upon a DNA lesion that inactivates Pol ß and its back up BER enzyme, DNA polymerase λ (Pol λ). Using this molecule as a starting point, we characterized an irreversible inhibitor (13) of Pol ß (IC = 0.4 µM) and Pol λ (IC = 0.25 µM) from a 130-member library of candidates that is ∼50-fold more effective against Pol ß. Pro-13 (5 µM) is only slightly cytotoxic to human cervical cancer cells (HeLa) but potentiates the cytotoxicity of methyl methanesulfonate (MMS). DNA isolated from HeLa cells treated with MMS contains a ∼3-fold greater amount of abasic sites when pro-13 is present, consistent with inhibition of DNA repair. Proinhibitor pro-13 continues to induce cytotoxicity in DNA damaged cells following MMS removal. HeLa cell cytotoxicity is increased ∼100-fold following an 8 h incubation with pro-13 after cells were originally subjected to conditions under which 20% of the cells survive and reproduce. The potentiation of MMS cytotoxicity by pro-13 is greater than any previously reported BER enzyme repair inhibitor.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Dano ao DNA
DNA Polimerase beta/antagonistas & inibidores
Inibidores da Síntese de Ácido Nucleico/farmacologia
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Reparo do DNA/efeitos dos fármacos
Sinergismo Farmacológico
Células HeLa
Seres Humanos
Metanossulfonato de Metila/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Nucleic Acid Synthesis Inhibitors); AT5C31J09G (Methyl Methanesulfonate); EC 2.7.7.- (DNA Polymerase beta); EC 2.7.7.- (DNA polymerase beta2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00259


  2 / 2318 MEDLINE  
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[PMID]:28742144
[Au] Autor:Stortz JA; Serafim TD; Alsford S; Wilkes J; Fernandez-Cortes F; Hamilton G; Briggs E; Lemgruber L; Horn D; Mottram JC; McCulloch R
[Ad] Endereço:The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
[Ti] Título:Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
[So] Source:PLoS Pathog;13(7):e1006477, 2017 Jul.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect the life style of individual organisms. To identify genome maintenance pathways in a divergent eukaryote and important parasite, Trypanosoma brucei, we performed RNAi screens to identify genes important for survival following exposure to the alkylating agent methyl methanesulphonate. Amongst a cohort of broadly conserved and, therefore, early evolved repair pathways, we reveal multiple activities not so far examined functionally in T. brucei, including DNA polymerases, DNA helicases and chromatin factors. In addition, the screens reveal Trypanosoma- or kinetoplastid-specific repair-associated activities. We also provide focused analyses of repair-associated protein kinases and show that loss of at least nine, and potentially as many as 30 protein kinases, including a nuclear aurora kinase, sensitises T. brucei to alkylation damage. Our results demonstrate the potential for synthetic lethal genome-wide screening of gene function in T. brucei and provide an evolutionary perspective on the repair pathways that underpin effective responses to damage, with particular relevance for related kinetoplastid pathogens. By revealing that a large number of diverse T. brucei protein kinases act in the response to damage, we expand the range of eukaryotic signalling factors implicated in genome maintenance activities.
[Mh] Termos MeSH primário: Reparo do DNA
Genoma de Protozoário
Proteínas Quinases/genética
Proteínas de Protozoários/genética
Interferência de RNA
Trypanosoma brucei brucei/enzimologia
Trypanosoma brucei brucei/genética
[Mh] Termos MeSH secundário: Dano ao DNA/efeitos dos fármacos
Evolução Molecular
Metanossulfonato de Metila/análogos & derivados
Metanossulfonato de Metila/toxicidade
Mutagênicos/toxicidade
Proteínas Quinases/metabolismo
Proteínas de Protozoários/metabolismo
Trypanosoma brucei brucei/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutagens); 0 (Protozoan Proteins); 2949-92-0 (methyl methanethiosulfonate); AT5C31J09G (Methyl Methanesulfonate); EC 2.7.- (Protein Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006477


  3 / 2318 MEDLINE  
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[PMID]:28458162
[Au] Autor:Gervai JZ; Gálicza J; Szeltner Z; Zámborszky J; Szüts D
[Ad] Endereço:Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, Budapest, H-1117, Hungary.
[Ti] Título:A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance.
[So] Source:DNA Repair (Amst);54:46-54, 2017 06.
[Is] ISSN:1568-7856
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Post-translational modifications of Proliferating Cell Nuclear Antigen (PCNA) play a key role in regulating the bypass of DNA lesions during DNA replication. PCNA can be monoubiquitylated at lysine 164 by the RAD6-RAD18 ubiquitin ligase complex. Through this modification, PCNA can interact with low fidelity Y family DNA polymerases to promote translesion synthesis. Monoubiquitylated PCNA can be polyubiquitylated on lysine 63 of ubiquitin by a further ubiquitin-conjugating complex. This modification promotes a template switching bypass process in yeast, while its role in higher eukaryotes is less clear. We investigated the function of PCNA ubiquitylation using a PCNA mutant DT40 chicken B lymphoblastoma cell line, which is hypersensitive to DNA damaging agents such as methyl methanesulfonate (MMS), cisplatin or ultraviolet radiation (UV) due to the loss of PCNA modifications. In the PCNA mutant we also detected cell cycle arrest following UV treatment, a reduced rate of damage bypass through translesion DNA synthesis on synthetic UV photoproducts, and an increased rate of genomic mutagenesis following MMS treatment. PCNA-ubiquitin fusion proteins have been reported to mimic endogenous PCNA ubiquitylation. We found that the stable expression of a PCNA -ubiquitin fusion protein fully or partially rescued the observed defects of the PCNA mutant. The expression of a PCNA -ubiquitin fusion protein, on which the formation of lysine 63-linked polyubiquitin chains is not possible, similarly rescued the cell cycle arrest, DNA damage sensitivity, reduction of translesion synthesis and increase of MMS-induced genomic mutagenesis. Template switching bypass was not affected by the genetic elimination of PCNA polyubiquitylation, but it was reduced in the absence of the recombination proteins BRCA1 or XRCC3. Our study found no requirement for PCNA polyubiquitylation to protect cells from replication-stalling DNA damage.
[Mh] Termos MeSH primário: Galinhas/genética
Dano ao DNA
Reparo do DNA
Replicação do DNA
Antígeno Nuclear de Célula em Proliferação/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína BRCA1/metabolismo
Galinhas/metabolismo
DNA/efeitos dos fármacos
DNA/metabolismo
DNA/efeitos da radiação
Proteínas de Ligação a DNA/metabolismo
DNA Polimerase Dirigida por DNA/metabolismo
Seres Humanos
Metanossulfonato de Metila/toxicidade
Mutação de Sentido Incorreto
Antígeno Nuclear de Célula em Proliferação/química
Antígeno Nuclear de Célula em Proliferação/genética
Ubiquitinação
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (DNA-Binding Proteins); 0 (Proliferating Cell Nuclear Antigen); 0 (X-ray repair cross complementing protein 3); 9007-49-2 (DNA); AT5C31J09G (Methyl Methanesulfonate); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


  4 / 2318 MEDLINE  
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[PMID]:28886188
[Au] Autor:Margulies CM; Chaim IA; Mazumder A; Criscione J; Samson LD
[Ad] Endereço:Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
[Ti] Título:Alkylation induced cerebellar degeneration dependent on Aag and Parp1 does not occur via previously established cell death mechanisms.
[So] Source:PLoS One;12(9):e0184619, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alkylating agents are ubiquitous in our internal and external environments, causing DNA damage that contributes to mutations and cell death that can result in aging, tissue degeneration and cancer. Repair of methylated DNA bases occurs primarily through the base excision repair (BER) pathway, a multi-enzyme pathway initiated by the alkyladenine DNA glycosylase (Aag, also known as Mpg). Previous work demonstrated that mice treated with the alkylating agent methyl methanesulfonate (MMS) undergo cerebellar degeneration in an Aag-dependent manner, whereby increased BER initiation by Aag causes increased tissue damage that is dependent on activation of poly (ADP-ribose) polymerase 1 (Parp1). Here, we dissect the molecular mechanism of cerebellar granule neuron (CGN) sensitivity to MMS using primary ex vivo neuronal cultures. We first established a high-throughput fluorescent imaging method to assess primary neuron sensitivity to treatment with DNA damaging agents. Next, we verified that the alkylation sensitivity of CGNs is an intrinsic phenotype that accurately recapitulates the in vivo dependency of alkylation-induced CGN cell death on Aag and Parp1 activity. Finally, we show that MMS-induced CGN toxicity is independent of all the cellular events that have previously been associated with Parp-mediated toxicity, including mitochondrial depolarization, AIF translocation, calcium fluxes, and NAD+ consumption. We therefore believe that further investigation is needed to adequately describe all varieties of Parp-mediated cell death.
[Mh] Termos MeSH primário: Cerebelo/citologia
DNA Glicosilases/metabolismo
Neurônios/citologia
Neurônios/metabolismo
Poli(ADP-Ribose) Polimerase-1/metabolismo
[Mh] Termos MeSH secundário: Alquilantes/farmacologia
Alquilação/efeitos dos fármacos
Animais
Morte Celular/efeitos dos fármacos
Células Cultivadas
DNA Glicosilases/genética
Reparo do DNA/efeitos dos fármacos
Reparo do DNA/genética
Hibridização in Situ Fluorescente
Metanossulfonato de Metila/farmacologia
Camundongos
Poli(ADP-Ribose) Polimerase-1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkylating Agents); AT5C31J09G (Methyl Methanesulfonate); EC 2.4.2.30 (Parp1 protein, mouse); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 3.2.2.- (3-methyladenine-DNA glycosylase); EC 3.2.2.- (DNA Glycosylases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184619


  5 / 2318 MEDLINE  
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[PMID]:28850003
[Au] Autor:Fagundes GE; Damiani AP; Borges GD; Teixeira KO; Jesus MM; Daumann F; Ramlov F; Carvalho T; Leffa DD; Rohr P; Moraes De Andrade V
[Ad] Endereço:a Laboratory of Cellular and Molecular Biology (LABIM), Post-graduate Program in Health Sciences University of the Extreme South of Santa Catarina (UNESC) , Criciúma , SC , Brazil.
[Ti] Título:Effect of green juice and their bioactive compounds on genotoxicity induced by alkylating agents in mice.
[So] Source:J Toxicol Environ Health A;80(13-15):756-766, 2017.
[Is] ISSN:1528-7394
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Kale juice (Brassica oleracea L. var. acephala D.C.) is a reliable source of dietary carotenoids and typically contains the highest concentrations of lutein (LT) and beta-carotene (BC) among green leafy vegetables. As a result of their antioxidant properties, dietary carotenoids are postulated to decrease the risk of disease occurrence, particularly certain cancers. The present study aimed to (1) examine the genotoxic and antigenotoxic activity of natural and commercially available juices derived from Brassica oleracea and (2) assess influence of LT or BC against DNA damage induced by alkylating agents such as methyl methanesulfonate (MS) or cyclophosphamide (CP) in vivo in mice. Male Swiss mice were divided into groups of 6 animals, which were treated with water, natural, or commercial Brassica oleraceae juices (kale), LT, BC, MMS, or CP. After treatment, DNA damage was determined in peripheral blood lymphocytes using the comet assay. Results demonstrated that none of the Brassica oleraceae juices or carotenoids produced genotoxic effects. In all examined cell types, kale juices or carotenoids inhibited DNA damage induced by MMS or CP administered either pre- or posttreatment by 50 and 20%, respectively. Under our experimental conditions, kale leaf juices alone exerted no marked genotoxic or clastogenic effects. However, a significant decrease in DNA damage induced by MMS or CP was noted. This effect was most pronounced in groups that received juices, rather than carotenoids, suggesting that the synergy among constituents present in the food matrix may be more beneficial than the action of single compounds. Data suggest that the antigenotoxic properties of kale juices may be of therapeutic importance.
[Mh] Termos MeSH primário: Alquilantes/efeitos adversos
Sucos de Frutas e Vegetais
[Mh] Termos MeSH secundário: Animais
Brassica/química
Cromatografia Líquida de Alta Pressão
Ensaio Cometa
Ciclofosfamida/antagonistas & inibidores
Ciclofosfamida/farmacologia
Dano ao DNA/efeitos dos fármacos
Sucos de Frutas e Vegetais/análise
Luteína/análise
Luteína/farmacologia
Masculino
Metanossulfonato de Metila/antagonistas & inibidores
Metanossulfonato de Metila/farmacologia
Camundongos
Mutagênicos/efeitos adversos
Mutagênicos/análise
beta Caroteno/análise
beta Caroteno/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkylating Agents); 0 (Mutagens); 01YAE03M7J (beta Carotene); 8N3DW7272P (Cyclophosphamide); AT5C31J09G (Methyl Methanesulfonate); X72A60C9MT (Lutein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1080/15287394.2017.1357307


  6 / 2318 MEDLINE  
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[PMID]:28806726
[Au] Autor:Iyer DR; Rhind N
[Ad] Endereço:Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
[Ti] Título:Replication fork slowing and stalling are distinct, checkpoint-independent consequences of replicating damaged DNA.
[So] Source:PLoS Genet;13(8):e1006958, 2017 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions, we have analyzed the checkpoint in the fission yeast Schizosaccharomyces pombe using a single-molecule DNA combing assay, which allows us to unambiguously separate the contribution of origin and fork regulation towards replication slowing, and allows us to investigate the behavior of individual forks. Moreover, we have interrogated the role of forks interacting with individual sites of damage by using three damaging agents-MMS, 4NQO and bleomycin-that cause similar levels of replication slowing with very different frequency of DNA lesions. We find that the checkpoint slows replication by inhibiting origin firing, but not by decreasing fork rates. However, the checkpoint appears to facilitate replication of damaged templates, allowing forks to more quickly pass lesions. Finally, using a novel analytic approach, we rigorously identify fork stalling events in our combing data and show that they play a previously unappreciated role in shaping replication kinetics in response to DNA damage.
[Mh] Termos MeSH primário: Dano ao DNA
Replicação do DNA
Regulação Fúngica da Expressão Gênica
Pontos de Checagem da Fase S do Ciclo Celular
Schizosaccharomyces/genética
[Mh] Termos MeSH secundário: 4-Nitroquinolina-1-Óxido
Bleomicina
DNA Fúngico/genética
Metanossulfonato de Metila
Proteína de Replicação A/genética
Proteína de Replicação A/metabolismo
Proteínas de Schizosaccharomyces pombe/genética
Proteínas de Schizosaccharomyces pombe/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (Replication Protein A); 0 (Schizosaccharomyces pombe Proteins); 11056-06-7 (Bleomycin); 56-57-5 (4-Nitroquinoline-1-oxide); AT5C31J09G (Methyl Methanesulfonate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006958


  7 / 2318 MEDLINE  
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[PMID]:28755435
[Au] Autor:Townsend TA; Parrish MC; Engelward BP; Manjanatha MG
[Ad] Endereço:Division of Genetic and Molecular Toxicology, United States Food & Drug Administration, National Center for Toxicological Research, Jefferson, AR, USA.
[Ti] Título:The development and validation of EpiComet-Chip, a modified high-throughput comet assay for the assessment of DNA methylation status.
[So] Source:Environ Mol Mutagen;58(7):508-521, 2017 Aug.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA damage and alterations in global DNA methylation status are associated with multiple human diseases and are frequently correlated with clinically relevant information. Therefore, assessing DNA damage and epigenetic modifications, including DNA methylation, is critical for predicting human exposure risk of pharmacological and biological agents. We previously developed a higher-throughput platform for the single cell gel electrophoresis (comet) assay, CometChip, to assess DNA damage and genotoxic potential. Here, we utilized the methylation-dependent endonuclease, McrBC, to develop a modified alkaline comet assay, "EpiComet," which allows single platform evaluation of genotoxicity and global DNA methylation [5-methylcytosine (5-mC)] status of single-cell populations under user-defined conditions. Further, we leveraged the CometChip platform to create an EpiComet-Chip system capable of performing quantification across simultaneous exposure protocols to enable unprecedented speed and simplicity. This system detected global methylation alterations in response to exposures which included chemotherapeutic and environmental agents. Using EpiComet-Chip on 63 matched samples, we correctly identified single-sample hypermethylation (≥1.5-fold) at 87% (20/23), hypomethylation (≥1.25-fold) at 100% (9/9), with a 4% (2/54) false-negative rate (FNR), and 10% (4/40) false-positive rate (FPR). Using a more stringent threshold to define hypermethylation (≥1.75-fold) allowed us to correctly identify 94% of hypermethylation (17/18), but increased our FPR to 16% (7/45). The successful application of this novel technology will aid hazard identification and risk characterization of FDA-regulated products, while providing utility for investigating epigenetic modes of action of agents in target organs, as the assay is amenable to cultured cells or nucleated cells from any tissue. Environ. Mol. Mutagen. 58:508-521, 2017. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Ensaio Cometa/métodos
Dano ao DNA
Metilação de DNA/efeitos dos fármacos
Epigênese Genética/efeitos dos fármacos
Ensaios de Triagem em Larga Escala/métodos
[Mh] Termos MeSH secundário: Técnicas de Cultura de Células
Células HeLa
Células Hep G2
Seres Humanos
Células MCF-7
Metanossulfonato de Metila/toxicidade
Mutagênicos/toxicidade
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutagens); AT5C31J09G (Methyl Methanesulfonate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE
[do] DOI:10.1002/em.22101


  8 / 2318 MEDLINE  
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[PMID]:28732331
[Au] Autor:Habas K; Najafzadeh M; Baumgartner A; Brinkworth MH; Anderson D
[Ad] Endereço:Division of Medical Sciences, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford, West Yorkshire, BD7 1DP, UK.
[Ti] Título:An evaluation of DNA damage in human lymphocytes and sperm exposed to methyl methanesulfonate involving the regulation pathways associated with apoptosis.
[So] Source:Chemosphere;185:709-716, 2017 Oct.
[Is] ISSN:1879-1298
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Exposure to DNA-damaging agents produces a range of stress-related responses. These change the expression of genes leading to mutations that cause cell cycle arrest, induction of apoptosis and cancer. We have examined the contribution of haploid and diploid DNA damage and genes involved in the regulation of the apoptotic process associated with exposure, The Comet assay was used to detect DNA damage and quantitative RT-PCR analysis (qPCR) to detect gene expression changes in lymphocytes and sperm in response to methyl methanesulfonate. In the Comet assay, cells were administered 0-1.2 mM of MMS at 37 °C for 30 min for lymphocytes and 32 °C for 60 min for sperm to obtain optimal survival for both cell types. In the Comet assay a significant increase in Olive tail moment (OTM) and % tail DNA indicated DNA damage at increasing concentrations compared to the control group. In the qPCR study, cells were treated for 4 h, and RNA was isolated at the end of the treatment. qPCR analysis of genes associated with DNA stress responses showed that TP53 and CDKN1A are upregulated, while BCL2 is downregulated compared with the control. Thus, MMS caused DNA damage in lymphocytes at increasing concentrations, but appeared not to have the same effect in sperm at the low concentrations. These results indicate that exposure to MMS increased DNA damage and triggered the apoptotic response by activating TP53, CDKN1A and BCL2. These findings of the processing of DNA damage in human lymphocytes and sperm should be taken into account when genotoxic alterations in both cell types are produced when monitoring human exposure.
[Mh] Termos MeSH primário: Dano ao DNA
Linfócitos/efeitos dos fármacos
Metanossulfonato de Metila/toxicidade
Mutagênicos/toxicidade
[Mh] Termos MeSH secundário: Apoptose
Ensaio Cometa
DNA/metabolismo
Reparo do DNA
Expressão Gênica
Seres Humanos
Masculino
Espermatozoides
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutagens); 9007-49-2 (DNA); AT5C31J09G (Methyl Methanesulfonate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE


  9 / 2318 MEDLINE  
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[PMID]:28542436
[Au] Autor:Boubriak II; Malhas AN; Drozdz MM; Pytowski L; Vaux DJ
[Ad] Endereço:Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
[Ti] Título:Stress-induced release of Oct-1 from the nuclear envelope is mediated by JNK phosphorylation of lamin B1.
[So] Source:PLoS One;12(5):e0177990, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The nuclear lamina can bind and sequester transcription factors (TFs), a function lost if the lamina is abnormal, with missing or mutant lamin proteins. We now show that TF sequestration is not all-or-nothing, but a dynamic physiological response to external signals. We show that the binding of the ubiquitous TF, Oct-1, to lamin B1 was reversed under conditions of cellular stress caused, inter alia, by the chemical methylating agent methylmethanesulfonate (MMS). A search for lamin B1 post-translational modifications that might mediate changes in Oct-1 binding using kinase inhibitors uncovered a role for c-Jun N-terminal kinase (JNK). Phosphoproteomic and site-directed mutagenesis analyses of lamin B1 isolated from control and MMS-treated nuclei identified T575 as a JNK site phosphorylated after stress. A new phospho-T575 specific anti-peptide antibody confirmed increased interphase cellular T575 phosphorylation after cell exposure to certain stress conditions, enabling us to conclude that lamin B1 acts as an interphase kinase target, releasing Oct-1 to execute a protective response to stress.
[Mh] Termos MeSH primário: Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Lamina Tipo B/metabolismo
Membrana Nuclear/metabolismo
Fator 1 de Transcrição de Octâmero/secreção
Estresse Fisiológico/fisiologia
[Mh] Termos MeSH secundário: Proteínas de Ciclo Celular/biossíntese
Linhagem Celular Tumoral
Células HeLa
Seres Humanos
Lamina Tipo A/metabolismo
Metanossulfonato de Metila/farmacologia
Mutagênese Sítio-Dirigida
Proteínas Nucleares/biossíntese
Fosforilação
Ligação Proteica
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (GADD45A protein, human); 0 (Lamin Type A); 0 (Lamin Type B); 0 (Nuclear Proteins); 0 (Octamer Transcription Factor-1); 0 (POU2F1 protein, human); 0 (SREBF1 protein, human); 0 (Sterol Regulatory Element Binding Protein 1); 0 (lamin B1); AT5C31J09G (Methyl Methanesulfonate); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177990


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[PMID]:28334815
[Au] Autor:Li F; Zheng LD; Chen X; Zhao X; Briggs SD; Du HN
[Ad] Endereço:Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
[Ti] Título:Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress.
[So] Source:Nucleic Acids Res;45(9):5183-5197, 2017 May 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover. We also determine that Rph1 and nuclear export protein Crm1 interact, which is required for Rph1 translocation from the nucleus to the cytoplasm. More importantly, Gcn5 directly acetylates Rph1 in vitro and in vivo, and Gcn5-containing complex, SAGA, is required for autophagic degradation of Rph1. Gcn5-mediated Rph1 acetylation is essential for the association of Rph1 with the nuclear pore protein Nup1. Finally, we show that sustaining high levels of Rph1 during DNA damage stress results in cell growth defects. Thus, we propose that Gcn5-mediated acetylation finely regulates Rph1 protein level and that autophagic degradation of Rph1 is important for cell homeostasis. Our findings may provide a general connection between DNA damage, protein acetylation and autophagy.
[Mh] Termos MeSH primário: Autofagia
Dano ao DNA
Histona Acetiltransferases/metabolismo
Histona Desmetilases/metabolismo
Proteólise
Proteínas Repressoras/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/citologia
Saccharomyces cerevisiae/metabolismo
Estresse Fisiológico
[Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Homeostase/efeitos dos fármacos
Carioferinas/metabolismo
Metanossulfonato de Metila/toxicidade
Modelos Biológicos
Fagossomos/efeitos dos fármacos
Fagossomos/metabolismo
Fosforilação/efeitos dos fármacos
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteólise/efeitos dos fármacos
Receptores Citoplasmáticos e Nucleares/metabolismo
Estresse Fisiológico/efeitos dos fármacos
Vacúolos/efeitos dos fármacos
Vacúolos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Karyopherins); 0 (RPH1 protein, S cerevisiae); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Repressor Proteins); 0 (Saccharomyces cerevisiae Proteins); 0 (exportin 1 protein); AT5C31J09G (Methyl Methanesulfonate); EC 1.14.11.- (Histone Demethylases); EC 2.3.1.48 (GCN5 protein, S cerevisiae); EC 2.3.1.48 (Histone Acetyltransferases); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx129



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