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[PMID]:29031774
[Au] Autor:Damsteegt EL; Davie A; Lokman PM
[Ad] Endereço:Department of Zoology, University of Otago, 340 Great King Street, PO Box 56, Dunedin 9054, New Zealand. Electronic address: erin.damsteegt@otago.ac.nz.
[Ti] Título:The evolution of apolipoprotein B and its mRNA editing complex. Does the lack of editing contribute to hypertriglyceridemia?
[So] Source:Gene;641:46-54, 2018 Jan 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The evolution of apolipoprotein B (Apob) has been intensely researched due to its importance during lipid transport. Mammalian full-length apob100 can be post-transcriptionally edited by the enzyme apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like complex-one (Apobec1) resulting in a truncated Apob, known as Apob48. Whilst both full-length and truncated forms of Apob are important for normal lipid homeostasis in mammals, there is no evidence for the presence of apob mRNA editing prior to the divergence of the mammals, yet, non-mammalian vertebrates appear to function normally with only Apob100. To date, the majority of the research carried out in non-mammalian vertebrates has focused on chickens with only a very limited number examining apob mRNA editing in fish. This study focused on the molecular evolution of Apobec1 and Apob in order to ascertain if apob mRNA editing occurs in eels, a basal teleost which represents an evolutionarily important animal group. No evidence for the presence of Apobec1 or the ability for eel apob to be edited was found. However, an important link between mutant mice and the evident hypertriglyceridemia in the plasma of non-mammalian vertebrates was made. This study has provided imperative evidence to help bridge the evolutionary gap between fish and mammals and provides further support for the lack of apob mRNA editing in non-mammalian vertebrates.
[Mh] Termos MeSH primário: Desaminases APOBEC/genética
Apolipoproteínas B/genética
Hipertrigliceridemia/genética
Edição de RNA/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Anguilla/genética
Animais
Mapeamento Cromossômico
Seres Humanos
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins B); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:28757211
[Au] Autor:Qiao Q; Wang L; Meng FL; Hwang JK; Alt FW; Wu H
[Ad] Endereço:Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:AID Recognizes Structured DNA for Class Switch Recombination.
[So] Source:Mol Cell;67(3):361-373.e4, 2017 Aug 03.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activation-induced cytidine deaminase (AID) initiates both class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. Mechanisms of AID targeting and catalysis remain elusive despite its critical immunological roles and off-target effects in tumorigenesis. Here, we produced active human AID and revealed its preferred recognition and deamination of structured substrates. G-quadruplex (G4)-containing substrates mimicking the mammalian immunoglobulin switch regions are particularly good AID substrates in vitro. By solving crystal structures of maltose binding protein (MBP)-fused AID alone and in complex with deoxycytidine monophosphate, we surprisingly identify a bifurcated substrate-binding surface that explains structured substrate recognition by capturing two adjacent single-stranded overhangs simultaneously. Moreover, G4 substrates induce cooperative AID oligomerization. Structure-based mutations that disrupt bifurcated substrate recognition or oligomerization both compromise CSR in splenic B cells. Collectively, our data implicate intrinsic preference of AID for structured substrates and uncover the importance of G4 recognition and oligomerization of AID in CSR.
[Mh] Termos MeSH primário: Citidina Desaminase/metabolismo
DNA/metabolismo
Switching de Imunoglobulina
Região de Troca de Imunoglobulinas
Recombinação Genética
[Mh] Termos MeSH secundário: Desaminases APOBEC/genética
Desaminases APOBEC/metabolismo
Animais
Diversidade de Anticorpos
Linfócitos B/enzimologia
Linfócitos B/imunologia
Citidina Desaminase/química
Citidina Desaminase/genética
DNA/química
DNA/genética
Seres Humanos
Camundongos
Modelos Moleculares
Mutação
Conformação de Ácido Nucleico
Ligação Proteica
Conformação Proteica
Baço/enzimologia
Baço/imunologia
Relação Estrutura-Atividade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.5.4.- (AICDA (activation-induced cytidine deaminase)); EC 3.5.4.5 (APOBEC Deaminases); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171007
[Lr] Data última revisão:
171007
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28479091
[Au] Autor:Ito F; Fu Y; Kao SA; Yang H; Chen XS
[Ad] Endereço:Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
[Ti] Título:Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins.
[So] Source:J Mol Biol;429(12):1787-1799, 2017 Jun 16.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins are a family of cytidine deaminases involved in various important biological processes such as antibody diversification/maturation, restriction of viral infection, and generation of somatic mutations. Catalytically active APOBEC proteins execute their biological functions mostly through deaminating cytosine (C) to uracil on single-stranded DNA/RNA. Activation-induced cytidine deaminase, one of the APOBEC members, was reported to deaminate methylated cytosine (mC) on DNA, and this mC deamination was proposed to be involved in the demethylation of mC for epigenetic regulation. The mC deamination activity is later demonstrated for APOBEC3A (A3A) and more recently for APOBEC3B and APOBEC3H (A3H). Despite extensive studies on APOBEC proteins, questions regarding whether the rest of APOBEC members have any mC deaminase activity and what are the relative deaminase activities for each APOBEC member remain unclear. Here, we performed a family-wide analysis of deaminase activities on C and mC by using purified recombinant proteins for 11 known human APOBEC proteins under similar conditions. Our comprehensive analyses revealed that each APOBEC has unique deaminase activity and selectivity for mC. A3A and A3H showed distinctively high deaminase activities on C and mC with relatively high selectivity for mC, whereas six other APOBEC members showed relatively low deaminase activity and selectivity for mC. Our mutational analysis showed that loop-1 of A3A is responsible for its high deaminase activity and selectivity for mC. These findings extend our understanding of APOBEC family proteins that have important roles in diverse biological functions and in genetic mutations.
[Mh] Termos MeSH primário: Desaminases APOBEC/metabolismo
Citosina/análogos & derivados
Citosina/metabolismo
[Mh] Termos MeSH secundário: Desaminases APOBEC/genética
Desaminases APOBEC/isolamento & purificação
Análise Mutacional de DNA
Desaminação
Seres Humanos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
8J337D1HZY (Cytosine); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE


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[PMID]:28365443
[Au] Autor:Liu X; Zhang M; Ying S; Zhang C; Lin R; Zheng J; Zhang G; Tian D; Guo Y; Du C; Chen Y; Chen S; Su X; Ji J; Deng W; Li X; Qiu S; Yan R; Xu Z; Wang Y; Guo Y; Cui J; Zhuang S; Yu H; Zheng Q; Marom M; Sheng S; Zhang G; Hu S; Li R; Su M
[Ad] Endereço:Institute of Clinical Pathology, Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
[Ti] Título:Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma.
[So] Source:Gastroenterology;153(1):166-177, 2017 Jul.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during the development of ESCC. We performed next-generation sequence analyses of esophageal nontumor, intraepithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. METHODS: We performed whole-genome, whole-exome, or targeted sequence analyses of 227 esophageal tissue samples from 70 patients with ESCC undergoing resection at Shantou University Medical College in China from 2012 through 2015 (no patients had received chemotherapy or radiation therapy); we analyzed normal tissues, tissues with simple hyperplasia, dysplastic tissues (IEN), and ESCC tissues collected from different regions of the esophagus at the same time. We also obtained 1191 nontumor esophageal biopsy specimens from the Chaoshan region (a high-risk region for ESCC) of China (a high-risk region for ESCC) and performed immunohistochemical and histologic analyses to detect inflammation. RESULTS: IEN and ESCC tissues had similar mutations and copy number alterations, at similar frequencies; these differed from mutations detected in tissues with simple hyperplasia. IEN tissues had mutations associated with apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like-mediated mutagenesis (a DNA damage mutational signature). Genetic analyses indicated that most ESCCs were formed from early stage IEN clones. Trunk mutations (mutations shared by >10% of paired IEN and ESCC tissues) were in genes that regulate DNA repair and cell apoptosis, proliferation and adhesion. Mutations in TP53 and CDKN2A and copy number alterations in 11q (contains CCND1), 3q (contains SOX2), 2q (contains NFE2L2), and 9p (contains CDKN2A) were considered to be trunk variants; these were dominant mutations detected at high frequencies in clones of paired IEN and ESCC samples. In the esophageal biopsy samples from high-risk individuals (residing in the Chaoshan region), 68.9% had an evidence of chronic inflammation; the level of inflammation was correlated with atypical cell structures and markers of DNA damage. CONCLUSIONS: We analyzed mutations and gene copy number changes in nontumor, IEN, and ESCC samples, collected from 70 patients. IEN and ESCCs each had similar mutations and markers of genomic instability, including apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like. Genomic changes observed in precancerous lesions might be used to identify patients at risk for ESCC.
[Mh] Termos MeSH primário: Carcinoma in Situ/genética
Carcinoma de Células Escamosas/genética
Neoplasias Esofágicas/genética
Esofagite/metabolismo
Esôfago/patologia
[Mh] Termos MeSH secundário: Desaminases APOBEC/genética
Apoptose/genética
Adesão Celular/genética
Proliferação Celular/genética
Cromossomos Humanos Par 11/genética
Cromossomos Humanos Par 2/genética
Cromossomos Humanos Par 3/genética
Cromossomos Humanos Par 9/genética
Inibidor de Quinase Dependente de Ciclina p18/genética
Variações do Número de Cópias de DNA
Análise Mutacional de DNA
Reparo do DNA/genética
Esofagite/patologia
Esôfago/metabolismo
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Hiperplasia/genética
Fator 2 Relacionado a NF-E2/genética
Filogenia
Fatores de Transcrição SOXB1/genética
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDKN2A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p18); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors); 0 (Tumor Suppressor Protein p53); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170403
[St] Status:MEDLINE


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[PMID]:28362825
[Au] Autor:Chen J; MacCarthy T
[Ad] Endereço:Department of Applied Mathematics and Statistics, Stony Brook University, Stony Book, New York, United States of America.
[Ti] Título:The preferred nucleotide contexts of the AID/APOBEC cytidine deaminases have differential effects when mutating retrotransposon and virus sequences compared to host genes.
[So] Source:PLoS Comput Biol;13(3):e1005471, 2017 Mar.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The AID / APOBEC genes are a family of cytidine deaminases that have evolved in vertebrates, and particularly mammals, to mutate RNA and DNA at distinct preferred nucleotide contexts (or "hotspots") on foreign genomes such as viruses and retrotransposons. These enzymes play a pivotal role in intrinsic immunity defense mechanisms, often deleteriously mutating invading retroviruses or retrotransposons and, in the case of AID, changing antibody sequences to drive affinity maturation. We investigate the strength of various hotspots on their known biological targets by evaluating the potential impact of mutations on the DNA coding sequences of these targets, and compare these results to hypothetical hotspots that did not evolve. We find that the existing AID / APOBEC hotspots have a large impact on retrotransposons and non-mammalian viruses while having a much smaller effect on vital mammalian genes, suggesting co-evolution with AID / APOBECs may have had an impact on the genomes of the viruses we analyzed. We determine that GC content appears to be a significant, but not sole, factor in resistance to deaminase activity. We discuss possible mechanisms AID and APOBEC viral targets have adopted to escape the impacts of deamination activity, including changing the GC content of the genome.
[Mh] Termos MeSH primário: Desaminases APOBEC/genética
Modelos Genéticos
[Mh] Termos MeSH secundário: Desaminases APOBEC/química
Desaminases APOBEC/metabolismo
Motivos de Aminoácidos
Animais
Composição de Bases
Códon
Biologia Computacional
Genoma Viral
Interações Hospedeiro-Patógeno/genética
Seres Humanos
Mutação
Retroelementos/genética
Retroviridae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon); 0 (Retroelements); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170909
[Lr] Data última revisão:
170909
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005471


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[PMID]:28331087
[Au] Autor:Yoshikawa R; Takeuchi JS; Yamada E; Nakano Y; Misawa N; Kimura Y; Ren F; Miyazawa T; Koyanagi Y; Sato K
[Ad] Endereço:Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
[Ti] Título:Feline Immunodeficiency Virus Evolutionarily Acquires Two Proteins, Vif and Protease, Capable of Antagonizing Feline APOBEC3.
[So] Source:J Virol;91(11), 2017 Jun 01.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The interplay between viral and host proteins has been well studied to elucidate virus-host interactions and their relevance to virulence. Mammalian genes encode apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins, which act as intrinsic restriction factors against lentiviruses. To overcome APOBEC3-mediated antiviral actions, lentiviruses have evolutionarily acquired an accessory protein, viral infectivity factor (Vif), and Vif degrades host APOBEC3 proteins via a ubiquitin/proteasome-dependent pathway. Although the Vif-APOBEC3 interaction and its evolutionary significance, particularly those of primate lentiviruses (including HIV) and primates (including humans), have been well investigated, those of nonprimate lentiviruses and nonprimates are poorly understood. Moreover, the factors that determine lentiviral pathogenicity remain unclear. Here, we focus on feline immunodeficiency virus (FIV), a pathogenic lentivirus in domestic cats, and the interaction between FIV Vif and feline APOBEC3 in terms of viral virulence and evolution. We reveal the significantly reduced diversity of FIV subtype B compared to that of other subtypes, which may associate with the low pathogenicity of this subtype. We also demonstrate that FIV subtype B Vif is less active with regard to feline APOBEC3 degradation. More intriguingly, we further reveal that FIV protease cleaves feline APOBEC3 in released virions. Taken together, our findings provide evidence that a lentivirus encodes two types of anti-APOBEC3 factors, Vif and viral protease. During the history of mammalian evolution, mammals coevolved with retroviruses, including lentiviruses. All pathogenic lentiviruses, excluding equine infectious anemia virus, have acquired the gene via evolution to combat APOBEC3 proteins, which are intrinsic restriction factors against exogenous lentiviruses. Here we demonstrate that FIV, a pathogenic lentivirus in domestic cats, antagonizes feline APOBEC3 proteins by both Vif and a viral protease. Furthermore, the Vif proteins of an FIV subtype (subtype B) have attenuated their anti-APOBEC3 activity through evolution. Our findings can be a clue to elucidate the complicated evolutionary processes by which lentiviruses adapt to mammals.
[Mh] Termos MeSH primário: Desaminases APOBEC/antagonistas & inibidores
Ácido Aspártico Endopeptidases/metabolismo
Produtos do Gene vif/metabolismo
Vírus da Imunodeficiência Felina/genética
[Mh] Termos MeSH secundário: Desaminases APOBEC/metabolismo
Animais
Ácido Aspártico Endopeptidases/genética
Gatos
Evolução Molecular
Produtos do Gene vif/genética
Interações Hospedeiro-Patógeno
Vírus da Imunodeficiência Felina/metabolismo
Vírus da Imunodeficiência Felina/patogenicidade
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gene Products, vif); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (FIV protease); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170727
[Lr] Data última revisão:
170727
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE


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[PMID]:28260788
[Au] Autor:Li Z; Abraham BJ; Berezovskaya A; Farah N; Liu Y; Leon T; Fielding A; Tan SH; Sanda T; Weintraub AS; Li B; Shen S; Zhang J; Mansour MR; Young RA; Look AT
[Ad] Endereço:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
[Ti] Título:APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL.
[So] Source:Leukemia;31(10):2057-2064, 2017 Oct.
[Is] ISSN:1476-5551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.
[Mh] Termos MeSH primário: Desaminases APOBEC/metabolismo
Proteínas de Ligação a DNA/biossíntese
Elementos Facilitadores Genéticos/genética
Regulação Leucêmica da Expressão Gênica/genética
Proteínas com Domínio LIM/biossíntese
Proteínas de Neoplasias/biossíntese
Mutação Puntual
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Fatores de Transcrição/biossíntese
Transcriptoma
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas/genética
Sequência de Bases
Sítios de Ligação
Linhagem Celular Tumoral
Criança
Imunoprecipitação da Cromatina
DNA de Neoplasias/genética
Proteínas de Ligação a DNA/genética
Genes myb
Seres Humanos
Células Jurkat
Proteínas com Domínio LIM/genética
Proteínas de Neoplasias/genética
Polimorfismo de Nucleotídeo Único
Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo
Proteínas Proto-Oncogênicas c-myb/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-myb/genética
Proteínas Proto-Oncogênicas c-myb/metabolismo
Interferência de RNA
RNA Interferente Pequeno/genética
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (DNA, Neoplasm); 0 (DNA-Binding Proteins); 0 (LIM Domain Proteins); 0 (LMO1 protein, human); 0 (Neoplasm Proteins); 0 (Proto-Oncogene Proteins c-myb); 0 (RNA, Small Interfering); 0 (Transcription Factors); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE
[do] DOI:10.1038/leu.2017.75


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[PMID]:27811275
[Au] Autor:Alexandrov LB; Ju YS; Haase K; Van Loo P; Martincorena I; Nik-Zainal S; Totoki Y; Fujimoto A; Nakagawa H; Shibata T; Campbell PJ; Vineis P; Phillips DH; Stratton MR
[Ad] Endereço:Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, USA. lba@lanl.gov mrs@sanger.ac.uk.
[Ti] Título:Mutational signatures associated with tobacco smoking in human cancer.
[So] Source:Science;354(6312):618-622, 2016 11 04.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.
[Mh] Termos MeSH primário: Carcinógenos/toxicidade
Metilação de DNA
Mutação
Neoplasias/induzido quimicamente
Neoplasias/genética
Fumar/genética
Tabaco/toxicidade
[Mh] Termos MeSH secundário: Desaminases APOBEC/metabolismo
Ilhas de CpG
Dano ao DNA
Exoma/genética
Seres Humanos
Neoplasias/epidemiologia
Risco
Fumar/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Carcinogens); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27585283
[Au] Autor:Siriwardena SU; Chen K; Bhagwat AS
[Ad] Endereço:Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
[Ti] Título:Functions and Malfunctions of Mammalian DNA-Cytosine Deaminases.
[So] Source:Chem Rev;116(20):12688-12710, 2016 10 26.
[Is] ISSN:1520-6890
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced during the body's inflammatory response to infections, and they help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport. Members of the APOBEC3 subfamily in humans (APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H) inhibit infections of viruses such as HIV-1, HBV, and HCV, and retrotransposition of endogenous retroelements through mutagenic and nonmutagenic mechanisms. There is emerging consensus that these enzymes can cause mutations in the cellular genome at replication forks or within transcription bubbles depending on the physiological state of the cell and the phase of the cell cycle during which they are expressed. We describe here the state of knowledge about the structures of these enzymes, regulation of their expression, and both the advantageous and deleterious consequences of their expression, including carcinogenesis. We highlight similarities among them and present a holistic view of their regulation and function.
[Mh] Termos MeSH primário: Citidina Desaminase/metabolismo
DNA/metabolismo
[Mh] Termos MeSH secundário: Desaminases APOBEC/metabolismo
Animais
Mamíferos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.5.4.- (AICDA (activation-induced cytidine deaminase)); EC 3.5.4.5 (APOBEC Deaminases); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160902
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrev.6b00296


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[PMID]:27582092
[Au] Autor:Thomsen MB; Nordentoft I; Lamy P; Høyer S; Vang S; Hedegaard J; Borre M; Jensen JB; Ørntoft TF; Dyrskjøt L
[Ad] Endereço:Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
[Ti] Título:Spatial and temporal clonal evolution during development of metastatic urothelial carcinoma.
[So] Source:Mol Oncol;10(9):1450-1460, 2016 Nov.
[Is] ISSN:1878-0261
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients with metastatic bladder cancer have a median survival of only 13-14 months. Precision medicine using targeted therapy may improve survival. Here we investigated spatial and temporal tumour evolution and tumour heterogeneity in order to evaluate the potential use of targeted treatment of metastatic bladder cancer. We performed a proof-of-concept study by whole exome sequencing of multiple tumour regions (n = 22) from three patients with metastatic bladder cancer. DNA from primary and metastatic tumour biopsies was analysed for mutations using Mutect and potential therapeutic targets were identified. We identified 256, 265 and 378 somatic mutations per patient, encompassing mutations with an estimated functional impact in 6-12 known disease driver genes per patient. Disease driver mutations present in all tumour regions could be identified in all cases, however, over time metastasis specific driver mutations emerged. For each patient we identified 6-10 potentially therapeutic targets, however very few targets were present in all regions. Low mutational allele frequencies were observed in most regions suggesting a complex mixture of different cancer cells with no spatial demarcation of subclones. In conclusion, primary bladder tumours and metastatic lesions showed heterogeneity at the molecular level, but within the primary tumour the heterogeneity appeared low. The observed lack of potential therapeutic targets common to all cancer cells in primary tumours and metastases emphasizes the challenges in designing rational targeted therapy solely based on analysis of the primary tumours.
[Mh] Termos MeSH primário: Evolução Clonal/genética
Neoplasias da Bexiga Urinária/genética
Neoplasias da Bexiga Urinária/patologia
Urotélio/patologia
[Mh] Termos MeSH secundário: Desaminases APOBEC/metabolismo
Progressão da Doença
Frequência do Gene/genética
Seres Humanos
Modelos Biológicos
Mutagênese/genética
Mutação/genética
Metástase Neoplásica
Filogenia
Análise de Sequência de DNA
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160902
[St] Status:MEDLINE



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