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[PMID]:29227074
[Au] Autor:Minchenko OH; Tsymbal DO; Minchenko DO; Riabovol OO; Ratushna OO; Karbovskyi LL
[Ti] Título:Hypoxic regulation of the expression of cell proliferation related genes in U87 glioma cells upon inhibition of ire1 signaling enzyme
[So] Source:Ukr Biochem J;88(1):11-21, 2016 Ja-Feb.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:We have studied the effect of inhibition of IRE1 (inositol requiring enzyme 1), which is a central mediator of endoplasmic reticulum stress and a controller of cell proliferation and tumor growth, on hypoxic regulation of the expression of different proliferation related genes in U87 glioma cells. It was shown that hypoxia leads to up-regulation of the expression of IL13RA2, CD24, ING1, ING2, ENDOG, and POLG genes and to down-regulation ­ of KRT18, TRAPPC3, TSFM, and MTIF2 genes at the mRNA level in control glioma cells. Changes for ING1 and CD24 genes were more significant. At the same time, inhibition of IRE1 modifies the effect of hypoxia on the expression of all studied genes. In particular, it increases sensitivity to hypoxia of the expression of IL13RA2, TRAPPC3, ENDOG, and PLOG genes and suppresses the effect of hypoxia on the expression of ING1 gene. Additionally, it eliminates hypoxic regulation of KRT18, CD24, ING2, TSFM, and MTIF2 genes expressions and introduces sensitivity to hypoxia of the expression of BET1 gene in glioma cells. The present study demonstrates that hypoxia, which often contributes to tumor growth, affects the expression of almost all studied genes. Additionally, inhibition of IRE1 can both enhance and suppress the hypoxic regulation of these gene expressions in a gene specific manner and thus possibly contributes to slower glioma growth, but several aspects of this regulation must be further clarified.
[Mh] Termos MeSH primário: Estresse do Retículo Endoplasmático/genética
Endorribonucleases/genética
Regulação Neoplásica da Expressão Gênica
Neuroglia/metabolismo
Proteínas Serina-Treonina Quinases/genética
RNA Mensageiro/genética
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Antígeno CD24/genética
Antígeno CD24/metabolismo
Hipóxia Celular
Linhagem Celular Tumoral
Proliferação Celular
DNA Polimerase gama/genética
DNA Polimerase gama/metabolismo
Endodesoxirribonucleases/genética
Endodesoxirribonucleases/metabolismo
Endorribonucleases/antagonistas & inibidores
Endorribonucleases/metabolismo
Fatores de Iniciação em Eucariotos/genética
Fatores de Iniciação em Eucariotos/metabolismo
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Proteína 1 Inibidora do Crescimento/genética
Proteína 1 Inibidora do Crescimento/metabolismo
Subunidade alfa2 de Receptor de Interleucina-13/genética
Subunidade alfa2 de Receptor de Interleucina-13/metabolismo
Queratina-18/genética
Queratina-18/metabolismo
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Neuroglia/patologia
Fatores de Alongamento de Peptídeos/genética
Fatores de Alongamento de Peptídeos/metabolismo
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Qc-SNARE/genética
Proteínas Qc-SNARE/metabolismo
RNA Mensageiro/metabolismo
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/metabolismo
Proteínas de Transporte Vesicular/genética
Proteínas de Transporte Vesicular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BET1L protein, human); 0 (CD24 Antigen); 0 (Eukaryotic Initiation Factors); 0 (Homeodomain Proteins); 0 (ING1 protein, human); 0 (ING2 protein, human); 0 (Inhibitor of Growth Protein 1); 0 (Interleukin-13 Receptor alpha2 Subunit); 0 (KRT18 protein, human); 0 (Keratin-18); 0 (MTIF2 protein, human); 0 (Mitochondrial Proteins); 0 (Peptide Elongation Factors); 0 (Qc-SNARE Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear); 0 (TRAPPC3 protein, human); 0 (TSFM protein, human); 0 (Tumor Suppressor Proteins); 0 (Vesicular Transport Proteins); EC 2.7.11.1 (ERN1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (POLG protein, human); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endoribonucleases); EC 3.1.21.- (endonuclease G)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.01.011


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[PMID]:28506336
[Au] Autor:Zhang YF; Wang JT; Gao JB; Lyu YY; Liang JM; Jia FY; Chen YB; Hao YP
[Ad] Endereço:Department of Pediatric Neurology, First Hospital of Jilin University, Changchun 130021, China.
[Ti] Título:[Alpers-Huttenlocher syndrome caused by a novel compound heterozygous mutation of POLG gene: a case report].
[So] Source:Zhongguo Dang Dai Er Ke Za Zhi;19(5):498-501, 2017 May.
[Is] ISSN:1008-8830
[Cp] País de publicação:China
[La] Idioma:chi
[Mh] Termos MeSH primário: DNA Polimerase Dirigida por DNA/genética
Esclerose Cerebral Difusa de Schilder/genética
Mutação
[Mh] Termos MeSH secundário: DNA Polimerase gama
Esclerose Cerebral Difusa de Schilder/diagnóstico
Esclerose Cerebral Difusa de Schilder/tratamento farmacológico
Esclerose Cerebral Difusa de Schilder/etiologia
Heterozigoto
Seres Humanos
Lactente
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human)
[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:170517
[St] Status:MEDLINE


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[PMID]:28430993
[Au] Autor:Siibak T; Clemente P; Bratic A; Bruhn H; Kauppila TES; Macao B; Schober FA; Lesko N; Wibom R; Naess K; Nennesmo I; Wedell A; Peter B; Freyer C; Falkenberg M; Wredenberg A
[Ad] Endereço:Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405?30, Sweden.
[Ti] Título:A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma.
[So] Source:Hum Mol Genet;26(13):2515-2525, 2017 Jul 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.
[Mh] Termos MeSH primário: DNA Polimerase Dirigida por DNA/genética
DNA Polimerase Dirigida por DNA/metabolismo
[Mh] Termos MeSH secundário: Adulto
Sequência de Aminoácidos
Animais
DNA Polimerase gama
Replicação do DNA/genética
DNA Mitocondrial/genética
Modelos Animais de Doenças
Drosophila melanogaster/genética
Feminino
Seres Humanos
Lactente
Mitocôndrias/genética
Mutação/genética
Oftalmoplegia Externa Progressiva Crônica/enzimologia
Linhagem
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[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:170422
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx146


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[PMID]:28242328
[Au] Autor:Lillenes MS; Støen M; Günther CC; Selnes P; Stenset VT; Espeseth T; Reinvang I; Fladby T; Tønjum T
[Ad] Endereço:Department of Microbiology, Healthy Brain Aging Centre (HBAC), Oslo University Hospital, Postbox 4950 Nydalen, 0424 Oslo, Norway; Department of Microbiology, Healthy Brain Aging Centre (HBAC), University of Oslo, 1078 Blindern, PO 0316, Norway. Electronic address: m.s.lillenes@medisin.uio.no.
[Ti] Título:Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance.
[So] Source:Neurosci Lett;645:46-52, 2017 04 03.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer's disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Transtornos Cognitivos/genética
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética
Proteínas de Ligação a DNA/genética
Proteínas Mitocondriais/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Alelos
Doença de Alzheimer/psicologia
Peptídeos beta-Amiloides/líquido cefalorraquidiano
Biomarcadores/líquido cefalorraquidiano
Estudos de Casos e Controles
Transtornos Cognitivos/psicologia
Dano ao DNA/genética
DNA Polimerase gama
Reparo do DNA/genética
DNA Polimerase Dirigida por DNA/genética
Estudos de Associação Genética
Predisposição Genética para Doença
Heterozigoto
Seres Humanos
Meia-Idade
Polimorfismo de Nucleotídeo Único
Espécies Reativas de Oxigênio/metabolismo
Proteínas tau/líquido cefalorraquidiano
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Biomarkers); 0 (DNA-Binding Proteins); 0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (TFAM protein, human); 0 (Transcription Factors); 0 (tau Proteins); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human); EC 4.2.99.18 (APEX1 protein, human); EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)
[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:170301
[St] Status:MEDLINE


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[PMID]:28207748
[Au] Autor:Berglund AK; Navarrete C; Engqvist MK; Hoberg E; Szilagyi Z; Taylor RW; Gustafsson CM; Falkenberg M; Clausen AR
[Ad] Endereço:Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
[Ti] Título:Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA.
[So] Source:PLoS Genet;13(2):e1006628, 2017 Feb.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and in the present study we use a genome-wide approach to precisely map the location of these. We find that ribonucleotides are distributed evenly between the heavy- and light-strand of mtDNA. The relative levels of incorporated ribonucleotides reflect that DNA polymerase γ discriminates the four ribonucleotides differentially during DNA synthesis. The observed pattern is also dependent on the mitochondrial deoxyribonucleotide (dNTP) pools and disease-causing mutations that change these pools alter both the absolute and relative levels of incorporated ribonucleotides. Our analyses strongly suggest that DNA polymerase γ-dependent incorporation is the main source of ribonucleotides in mtDNA and argues against the existence of a mitochondrial ribonucleotide excision repair pathway in human cells. Furthermore, we clearly demonstrate that when dNTP pools are limiting, ribonucleotides serve as a source of building blocks to maintain DNA replication. Increased levels of embedded ribonucleotides in patient cells with disturbed nucleotide pools may contribute to a pathogenic mechanism that affects mtDNA stability and impair new rounds of mtDNA replication.
[Mh] Termos MeSH primário: Reparo do DNA/genética
DNA Mitocondrial/genética
DNA Polimerase Dirigida por DNA/genética
Ribonucleotídeos/genética
[Mh] Termos MeSH secundário: DNA/biossíntese
DNA Polimerase gama
Replicação do DNA/genética
Fibroblastos
Genoma Mitocondrial
Células HeLa
Seres Humanos
Mitocôndrias/genética
Mitocôndrias/patologia
RNA/biossíntese
Ribonucleases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); 0 (Ribonucleotides); 63231-63-0 (RNA); 9007-49-2 (DNA); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 3.1.- (Ribonucleases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006628


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[PMID]:28206745
[Au] Autor:Euro L; Haapanen O; Róg T; Vattulainen I; Suomalainen A; Sharma V
[Ad] Endereço:Research Programs Unit, Molecular Neurology, University of Helsinki , 00290 Helsinki, Finland.
[Ti] Título:Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis.
[So] Source:Biochemistry;56(9):1227-1238, 2017 Mar 07.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA polymerase γ (Pol γ) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions, and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report the first atomistic classical molecular dynamics simulations of the human Pol γ replicative complex. Our simulation data show that DNA binding triggers remarkable changes in the enzyme structure, including (1) completion of the DNA-binding channel via a dynamic subdomain, which in the apo form blocks the catalytic site, (2) stabilization of the structure through the distal accessory ß-subunit, and (3) formation of a putative transient replisome-binding platform in the "intrinsic processivity" subdomain of the enzyme. Our data indicate that noncatalytic mutations may disrupt replisomal interactions, thereby causing Pol γ-associated neurodegenerative disorders.
[Mh] Termos MeSH primário: DNA Polimerase Dirigida por DNA/química
DNA Polimerase Dirigida por DNA/metabolismo
Mitocôndrias/enzimologia
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Domínio Catalítico
DNA/metabolismo
DNA Polimerase gama
Seres Humanos
Mutação
Doenças Neurodegenerativas/enzimologia
Doenças Neurodegenerativas/genética
Estrutura Secundária de Proteína
Rotação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b00934


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[PMID]:28187756
[Au] Autor:Soini HK; Väisänen A; Kärppä M; Hinttala R; Kytövuori L; Moilanen JS; Uusimaa J; Majamaa K
[Ad] Endereço:Research Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland. heidi.soini@oulu.fi.
[Ti] Título:A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease.
[So] Source:BMC Med Genet;18(1):14, 2017 Feb 10.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. METHODS: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions. RESULTS: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered. CONCLUSIONS: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations.
[Mh] Termos MeSH primário: DNA Mitocondrial/genética
Doenças Mitocondriais/genética
[Mh] Termos MeSH secundário: Sequência de Bases
DNA Polimerase gama
DNA Mitocondrial/classificação
DNA Mitocondrial/metabolismo
DNA Polimerase Dirigida por DNA/genética
Eletroforese em Gel de Poliacrilamida
Feminino
Haplótipos
Seres Humanos
Masculino
Meia-Idade
Doenças Mitocondriais/patologia
Conformação de Ácido Nucleico
Fases de Leitura Aberta/genética
Filogenia
Deleção de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0377-8


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[PMID]:28154168
[Au] Autor:DeBalsi KL; Longley MJ; Hoff KE; Copeland WC
[Ad] Endereço:From the Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
[Ti] Título:Synergistic Effects of the T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations.
[So] Source:J Biol Chem;292(10):4198-4209, 2017 Mar 10.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human mitochondrial DNA (mtDNA) polymerase γ (Pol γ) is the only polymerase known to replicate the mitochondrial genome. The Pol γ holoenzyme consists of the p140 catalytic subunit (POLG) and the p55 homodimeric accessory subunit (POLG2), which enhances binding of Pol γ to DNA and promotes processivity of the holoenzyme. Mutations within impede maintenance of mtDNA and cause mitochondrial diseases. Two common mutations usually found in patients primarily with progressive external ophthalmoplegia generate T251I and P587L amino acid substitutions. To determine whether T251I or P587L is the primary pathogenic allele or whether both substitutions are required to cause disease, we overproduced and purified WT, T251I, P587L, and T251I + P587L double variant forms of recombinant Pol γ. Biochemical characterization of these variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity, even in the presence of the p55 accessory subunit. However, physical association with p55 was unperturbed, suggesting intersubunit affinities similar to WT. Notably, although the single mutants were similarly impaired, a dramatic synergistic effect was found for the double mutant across all parameters. In conclusion, our analyses suggest that individually both T251I and P587L substitutions functionally impair Pol γ, with greater pathogenicity predicted for the single P587L variant. Combining T251I and P587L induces extreme thermal lability and leads to synergistic nucleotide and DNA binding defects, which severely impair catalytic activity and correlate with presentation of disease in patients.
[Mh] Termos MeSH primário: DNA Mitocondrial/metabolismo
DNA Polimerase Dirigida por DNA/genética
DNA Polimerase Dirigida por DNA/metabolismo
Mitocôndrias/patologia
Doenças Mitocondriais/patologia
Mutação/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos
Domínio Catalítico
Cristalografia por Raios X
DNA Polimerase gama
DNA Mitocondrial/genética
DNA Polimerase Dirigida por DNA/química
Seres Humanos
Cinética
Mitocôndrias/metabolismo
Doenças Mitocondriais/genética
Mutagênese Sítio-Dirigida
Conformação Proteica
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human)
[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:170204
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.773341


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[PMID]:28130605
[Au] Autor:Da Pozzo P; Cardaioli E; Rubegni A; Gallus GN; Malandrini A; Rufa A; Battisti C; Carluccio MA; Rocchi R; Giannini F; Bianchi A; Mancuso M; Siciliano G; Dotti MT; Federico A
[Ad] Endereço:Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100, Siena, Italy.
[Ti] Título:Novel POLG mutations and variable clinical phenotypes in 13 Italian patients.
[So] Source:Neurol Sci;38(4):563-570, 2017 Apr.
[Is] ISSN:1590-3478
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:POLG gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA (mtDNA) replication and repair. Mutations in POLG have been linked to a spectrum of clinical phenotypes, resulting in autosomal recessive or dominant mitochondrial diseases. These mutations have been associated with heterogeneous phenotypes, presenting with varying severity and at different ages of onset, ranging from the neonatal period to late adult life. We screened 13 patients for POLG mutations. All patients underwent a complete neurological examination, and in most of cases, muscle biopsy was performed. We detected 15 different variations in 13 unrelated Italian patients. Two mutations were novel and mapped in the pol domain (p.Thr989dup and p.Ala847Thr) of the enzyme. We also report new cases carrying controversial variations previously described as incompletely penetrant or a variant of unknown significance. Our study increases the range of clinical presentations associated with mutations in POLG gene, underlining some peculiar clinical features, such as PEO associated with corneal edema, and epilepsy, severe neuropathy with achalasia. The addition of two new substitutions, including the second report of an in-frame duplication, to the growing list of defects increases the value of POLG genetic diagnosis in a range of neurological presentations.
[Mh] Termos MeSH primário: DNA Polimerase Dirigida por DNA/genética
Doenças Mitocondriais/genética
Mutação
Fenótipo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Análise Mutacional de DNA
DNA Polimerase gama
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Seres Humanos
Itália
Masculino
Meia-Idade
Doenças Mitocondriais/patologia
Doenças Mitocondriais/fisiopatologia
Músculo Esquelético/patologia
Exame Neurológico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170129
[St] Status:MEDLINE
[do] DOI:10.1007/s10072-016-2734-3


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[PMID]:27845271
[Au] Autor:Liyanage SU; Coyaud E; Laurent EM; Hurren R; Maclean N; Wood SR; Kazak L; Shamas-Din A; Holt I; Raught B; Schimmer A
[Ad] Endereço:Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, ON, Canada.
[Ti] Título:Characterizing the mitochondrial DNA polymerase gamma interactome by BioID identifies Ruvbl2 localizes to the mitochondria.
[So] Source:Mitochondrion;32:31-35, 2017 Jan.
[Is] ISSN:1872-8278
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Human mitochondrial DNA (mtDNA) is replicated by the mitochondrial DNA polymerase gamma (POLG). Using proximity dependent biotin labelling (BioID), we characterized the POLG interactome and identified new interaction partners involved in mtDNA maintenance, transcription, translation and protein quality control. We also identified interaction with the nuclear AAA+ ATPase Ruvbl2, suggesting mitochondrial localization for this protein. Ruvbl2 was detected in mitochondria-enriched fractions in leukemic cells. Additionally, transgenic overexpression of Ruvbl2 from an alternative translation initiation site resulted in mitochondrial co-localization. Overall, POLG interactome mapping identifies novel proteins which support mitochondrial biogenesis and a potential novel mitochondrial isoform of Ruvbl2.
[Mh] Termos MeSH primário: Proteínas de Transporte/análise
DNA Helicases/análise
DNA Polimerase Dirigida por DNA/metabolismo
Mitocôndrias/química
Mapeamento de Interação de Proteínas
[Mh] Termos MeSH secundário: ATPases Associadas a Diversas Atividades Celulares
DNA Polimerase gama
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 2.7.7.7 (POLG protein, human); EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (RUVBL2 protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE



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