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Pesquisa : G05.360.340.024.340.137.430 [Categoria DeCS]
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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


  2 / 415 MEDLINE  
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[PMID]:28416601
[Au] Autor:Boyer F; Boutouil H; Dalloul I; Dalloul Z; Cook-Moreau J; Aldigier JC; Carrion C; Herve B; Scaon E; Cogné M; Péron S
[Ad] Endereço:Université de Limoges, Contrôle de la Réponse Immune B et Lymphoproliférations, UMR 7276, F-87000 Limoges, France.
[Ti] Título:CSReport: A New Computational Tool Designed for Automatic Analysis of Class Switch Recombination Junctions Sequenced by High-Throughput Sequencing.
[So] Source:J Immunol;198(10):4148-4155, 2017 May 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:B cells ensure humoral immune responses due to the production of Ag-specific memory B cells and Ab-secreting plasma cells. In secondary lymphoid organs, Ag-driven B cell activation induces terminal maturation and Ig isotype class switch (class switch recombination [CSR]). CSR creates a virtually unique locus in every B cell clone by intrachromosomal recombination between two switch (S) regions upstream of each C region gene. Amount and structural features of CSR junctions reveal valuable information about the CSR mechanism, and analysis of CSR junctions is useful in basic and clinical research studies of B cell functions. To provide an automated tool able to analyze large data sets of CSR junction sequences produced by high-throughput sequencing (HTS), we designed CSReport, a software program dedicated to support analysis of CSR recombination junctions sequenced with a HTS-based protocol (Ion Torrent technology). CSReport was assessed using simulated data sets of CSR junctions and then used for analysis of Sµ-Sα and Sµ-Sγ1 junctions from CH12F3 cells and primary murine B cells, respectively. CSReport identifies junction segment breakpoints on reference sequences and junction structure (blunt-ended junctions or junctions with insertions or microhomology). Besides the ability to analyze unprecedentedly large libraries of junction sequences, CSReport will provide a unified framework for CSR junction studies. Our results show that CSReport is an accurate tool for analysis of sequences from our HTS-based protocol for CSR junctions, thereby facilitating and accelerating their study.
[Mh] Termos MeSH primário: Sequenciamento de Nucleotídeos em Larga Escala
Switching de Imunoglobulina/genética
Recombinação Genética
Software
[Mh] Termos MeSH secundário: Linfócitos B/imunologia
Quebras de DNA de Cadeia Dupla
Isotipos de Imunoglobulinas/genética
Região de Troca de Imunoglobulinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Isotypes)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601924


  3 / 415 MEDLINE  
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[PMID]:28188246
[Au] Autor:DiMenna LJ; Yen WF; Nicolas L; Sharma R; Saldanha ZN; Chaudhuri J
[Ad] Endereço:Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021; and.
[Ti] Título:Cutting Edge: The Transcription Factor Sox2 Regulates AID Expression in Class-Switched B Cells.
[So] Source:J Immunol;198(6):2244-2248, 2017 Mar 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:IgH class switch recombination (CSR) occurs through the deliberate introduction of activation-induced cytidine deaminase (AID)-instigated DNA double-strand breaks into the loci. Because double-strand breaks are generally highly toxic, mechanisms that regulate AID expression are of much relevance to CSR and genomic integrity; however, effectors of such regulatory processes are still poorly understood. In this article, we show that the transcription factor sex determining region Y-box 2 (Sox2) is expressed in activated B cells, but almost exclusively in those that have undergone CSR. We demonstrate that enforced expression of Sox2 in splenic B cells severely inhibits AID expression and CSR, whereas deletion of Sox2 increases the frequency of translocations. These results suggest that Sox2 may regulate AID expression in class-switched B cells to suppress genomic instability associated with CSR.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Citidina Desaminase/metabolismo
Genes myc/genética
Fatores de Transcrição SOXB1/metabolismo
Baço/imunologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Células Cultivadas
Citidina Desaminase/genética
Quebras de DNA de Cadeia Dupla
Instabilidade Genômica
Região de Troca de Imunoglobulinas
Ativação Linfocitária/genética
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fatores de Transcrição SOXB1/genética
Translocação Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SOXB1 Transcription Factors); 0 (Sox2 protein, mouse); EC 3.5.4.- (AICDA (activation-induced cytidine deaminase)); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1502266


  4 / 415 MEDLINE  
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[PMID]:27713077
[Au] Autor:Almejún MB; Campos BC; Patiño V; Galicchio M; Zelazko M; Oleastro M; Oppezzo P; Danielian S
[Ad] Endereço:Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr Juan P. Garrahan, Buenos Aires, Argentina. Electronic address: mbalmejun@gmail.com.
[Ti] Título:Noninfectious complications in patients with pediatric-onset common variable immunodeficiency correlated with defects in somatic hypermutation but not in class-switch recombination.
[So] Source:J Allergy Clin Immunol;139(3):913-922, 2017 Mar.
[Is] ISSN:1097-6825
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and usually presents with a normal quantity of peripheral B cells. Most attempts aiming to classify these patients have mainly been focused on T- or B-cell phenotypes and their ability to produce protective antibodies, but it is still a major challenge to find a suitable classification that includes the clinical and immunologic heterogeneity of these patients. OBJECTIVE: In this study we evaluated the late stages of B-cell differentiation in a heterogeneous population of patients with pediatric-onset CVID to clinically correlate and assess their ability to perform somatic hypermutation (SHM), class-switch recombination (CSR), or both. METHODS: We performed a previously reported assay, the restriction enzyme hotspot mutation assay (IgκREHMA), to evaluate in vivo SHM status. We amplified switch regions from genomic DNA to investigate the quality of the double-strand break repairs in the class-switch recombination process in vivo. We also tested the ability to generate immunoglobulin germline and circle transcripts and to upregulate the activation-induced cytidine deaminase gene through in vitro T-dependent and T-independent stimuli. RESULTS: Our results showed that patients could be classified into 2 groups according to their degree of SHM alteration. This stratification showed a significant association between patients of group A, severe alteration, and the presence of noninfectious complications. Additionally, 60% of patients presented with increased microhomology use at switched regions. In vitro activation revealed that patients with CVID behaved heterogeneously in terms of responsiveness to T-dependent stimuli. CONCLUSIONS: The correlation between noninfectious complications and SHM could be an important tool for physicians to further characterize patients with CVID. This categorization would help to improve elucidation of the complex mechanisms involved in B-cell differentiation pathways.
[Mh] Termos MeSH primário: Imunodeficiência de Variável Comum/genética
Imunodeficiência de Variável Comum/imunologia
[Mh] Termos MeSH secundário: Adolescente
Linfócitos B/imunologia
Criança
Pré-Escolar
Feminino
Seres Humanos
Região de Troca de Imunoglobulinas
Lactente
Leucócitos Mononucleares
Masculino
Recombinação Genética
Hipermutação Somática de Imunoglobulina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161008
[St] Status:MEDLINE


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[PMID]:27559052
[Au] Autor:Kim A; Han L; Santiago GE; Verdun RE; Yu K
[Ad] Endereço:Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824;
[Ti] Título:Class-Switch Recombination in the Absence of the IgH 3' Regulatory Region.
[So] Source:J Immunol;197(7):2930-5, 2016 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ∼28-kb 3' regulatory region (3'RR), which is located at the most distal 3' region of the Ig H chain locus, has multiple regulatory functions that control IgH expression, class-switch recombination (CSR), and somatic hypermutation. In this article, we report that deletion of the entire 3'RR in a mouse B cell line that is capable of robust cytokine-dependent CSR to IgA results in reduced, but not abolished, CSR. These data suggest that 3'RR is not absolutely required for CSR and, thus, is not essential for targeting activation-induced cytidine deaminase to S regions, as was suggested. Moreover, replacing 3'RR with a DNA fragment including only its four DNase I hypersensitive sites (lacking the large spacer regions) restores CSR to a level equivalent to or even higher than in wild-type cells, suggesting that the four hypersensitive sites contain most of the CSR-promoting functions of 3'RR. Stimulated cells express abundant germline transcripts, with the presence or absence of 3'RR, providing evidence that 3'RR has a role in promoting CSR that is unique from enhancing S region transcription.
[Mh] Termos MeSH primário: Imunoglobulina G/genética
Cadeias Pesadas de Imunoglobulinas/genética
Região de Troca de Imunoglobulinas/genética
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Imunoglobulina G/imunologia
Cadeias Pesadas de Imunoglobulinas/imunologia
Região de Troca de Imunoglobulinas/imunologia
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin G); 0 (Immunoglobulin Heavy Chains)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160826
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600530


  6 / 415 MEDLINE  
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[PMID]:27494228
[Au] Autor:Jones BG; Penkert RR; Xu B; Fan Y; Neale G; Gearhart PJ; Hurwitz JL
[Ad] Endereço:Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
[Ti] Título:Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression.
[So] Source:Mol Immunol;77:97-102, 2016 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ERα-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the JH cluster to Cδ, with peaks in Eµ and Sµ sites. Additional peaks of ERα binding were coincident with hs1,2 and hs4 sites in the 3' regulatory region (3'RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Regulação da Expressão Gênica/imunologia
Cadeias Pesadas de Imunoglobulinas/imunologia
Região de Troca de Imunoglobulinas/imunologia
Receptores Estrogênicos/imunologia
Elementos de Resposta/imunologia
[Mh] Termos MeSH secundário: Animais
Formação de Anticorpos/genética
Formação de Anticorpos/imunologia
Imunoprecipitação da Cromatina
Feminino
Seres Humanos
Ativação Linfocitária/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Reação em Cadeia da Polimerase
Receptores Estrogênicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Heavy Chains); 0 (Receptors, Estrogen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160806
[St] Status:MEDLINE


  7 / 415 MEDLINE  
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[PMID]:26799454
[Au] Autor:DiMenna LJ; Chaudhuri J
[Ad] Endereço:Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
[Ti] Título:Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination.
[So] Source:Eur J Immunol;46(3):523-30, 2016 Mar.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The mechanism by which the DNA deaminase activation-induced cytidine deaminase (AID) is specifically recruited to repetitive switch region DNA during class switch recombination is still poorly understood. Work over the past decade has revealed a strong link between transcription and RNA polymerase-associated factors in AID recruitment, yet none of these processes satisfactorily explain how AID specificity is affected. Here, we review a recent finding wherein AID is guided to switch regions not by a protein factor but by an RNA moiety, and especially one associated with a noncoding RNA that has been long thought of as being inert. This work explains the long-standing requirement of splicing of noncoding transcripts during class switching, and has implications in both B cell-mediated immunity as well as the underlying pathological syndromes associated with the recombination reaction.
[Mh] Termos MeSH primário: Citidina Desaminase/metabolismo
DNA/metabolismo
Switching de Imunoglobulina/genética
RNA/fisiologia
[Mh] Termos MeSH secundário: Animais
Citidina Desaminase/genética
Seres Humanos
Região de Troca de Imunoglobulinas/genética
Imunoglobulinas/genética
Camundongos
RNA/genética
Recombinação Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Immunoglobulins); 63231-63-0 (RNA); 9007-49-2 (DNA); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160123
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201545809


  8 / 415 MEDLINE  
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[PMID]:26527723
[Au] Autor:Yadav P; Owiti N; Kim N
[Ad] Endereço:Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
[Ti] Título:The role of topoisomerase I in suppressing genome instability associated with a highly transcribed guanine-rich sequence is not restricted to preventing RNA:DNA hybrid accumulation.
[So] Source:Nucleic Acids Res;44(2):718-29, 2016 Jan 29.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Highly transcribed guanine-run containing sequences, in Saccharomyces cerevisiae, become unstable when topoisomerase I (Top1) is disrupted. Topological changes, such as the formation of extended RNA:DNA hybrids or R-loops or non-canonical DNA structures including G-quadruplexes has been proposed as the major underlying cause of the transcription-linked genome instability. Here, we report that R-loop accumulation at a guanine-rich sequence, which is capable of assembling into the four-stranded G4 DNA structure, is dependent on the level and the orientation of transcription. In the absence of Top1 or RNase Hs, R-loops accumulated to substantially higher extent when guanine-runs were located on the non-transcribed strand. This coincides with the orientation where higher genome instability was observed. However, we further report that there are significant differences between the disruption of RNase Hs and Top1 in regards to the orientation-specific elevation in genome instability at the guanine-rich sequence. Additionally, genome instability in Top1-deficient yeasts is not completely suppressed by removal of negative supercoils and further aggravated by expression of mutant Top1. Together, our data provide a strong support for a function of Top1 in suppressing genome instability at the guanine-run containing sequence that goes beyond preventing the transcription-associated RNA:DNA hybrid formation.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo I/metabolismo
DNA Fúngico/metabolismo
Instabilidade Genômica
RNA Fúngico/metabolismo
[Mh] Termos MeSH secundário: Camptotecina
Replicação do DNA
DNA Topoisomerases Tipo I/genética
DNA Fúngico/química
DNA Fúngico/genética
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Quadruplex G
Teste de Complementação Genética
Guanina/química
Guanina/metabolismo
Região de Troca de Imunoglobulinas/genética
Hibridização de Ácido Nucleico
RNA Fúngico/genética
Recombinação Genética
Ribonuclease H/genética
Ribonuclease H/metabolismo
Saccharomyces cerevisiae/efeitos dos fármacos
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (Escherichia coli Proteins); 0 (RNA, Fungal); 0 (Saccharomyces cerevisiae Proteins); 5Z93L87A1R (Guanine); EC 3.1.26.4 (Ribonuclease H); EC 5.99.1.2 (DNA Topoisomerases, Type I); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151104
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkv1152


  9 / 415 MEDLINE  
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[PMID]:26277278
[Au] Autor:Zhang ZZ; Pannunzio NR; Lu Z; Hsu E; Yu K; Lieber MR
[Ad] Endereço:USC Norris Comprehensive Cancer Ctr. Molecular and Computational Biology Program, Department of Biological Sciences, Departments of Pathology, Biochemistry & Molecular Biology, Molecular Microbiology & Immunology, Urology, University of Southern California Keck School of Medicine, 1441 Eastl
[Ti] Título:The repetitive portion of the Xenopus IgH Mu switch region mediates orientation-dependent class switch recombination.
[So] Source:Mol Immunol;67(2 Pt B):524-31, 2015 Oct.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Vertebrates developed immunoglobulin heavy chain (IgH) class switch recombination (CSR) to express different IgH constant regions. Most double-strand breaks for Ig CSR occur within the repetitive portion of the switch regions located upstream of each set of constant domain exons for the Igγ, Igα or Igϵ heavy chain. Unlike mammalian switch regions, Xenopus switch regions do not have a high G-density on the non-template DNA strand. In previous studies, when Xenopus Sµ DNA was moved to the genome of mice, it is able to support substantial CSR when it is used to replace the murine Sγ1 region. Here, we tested both the 2kb repetitive portion and the 4.6 kb full-length portions of the Xenopus Sµ in both their natural (forward) orientation relative to the constant domain exons, as well as the opposite (reverse) orientation. Consistent with previous work, we find that the 4.6 kb full-length Sµ mediates similar levels of CSR in both the forward and reverse orientations. Whereas, the forward orientation of the 2kb portion can restore the majority of the CSR level of the 4.6 kb full-length Sµ, the reverse orientation poorly supports R-looping and no CSR. The forward orientation of the 2kb repetitive portion has more GG dinucleotides on the non-template strand than the reverse orientation. The correlation of R-loop formation with CSR efficiency, as demonstrated in the 2kb repetitive fragment of the Xenopus switch region, confirms a role played by R-looping in CSR that appears to be conserved through evolution.
[Mh] Termos MeSH primário: Switching de Imunoglobulina/imunologia
Cadeias Pesadas de Imunoglobulinas/imunologia
Região de Troca de Imunoglobulinas/imunologia
Cadeias mu de Imunoglobulina/imunologia
Sequências Repetitivas de Aminoácidos
Xenopus/imunologia
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Animais
Cadeias Pesadas de Imunoglobulinas/química
Região de Troca de Imunoglobulinas/genética
Cadeias mu de Imunoglobulina/química
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Immunoglobulin Heavy Chains); 0 (Immunoglobulin mu-Chains)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170209
[Lr] Data última revisão:
170209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150817
[St] Status:MEDLINE


  10 / 415 MEDLINE  
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[PMID]:26267846
[Au] Autor:Kadungure T; Ucher AJ; Linehan EK; Schrader CE; Stavnezer J
[Ad] Endereço:Department of Microbiology and Physiological Systems, Univ. of Massachusetts Medical School, Worcester, MA, 01605, United States of America.
[Ti] Título:Individual substitution mutations in the AID C terminus that ablate IgH class switch recombination.
[So] Source:PLoS One;10(8):e0134397, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activation-induced cytidine deaminase (AID) is essential for class switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes. The C terminus of AID is required for CSR but not for SHM, but the reason for this is not entirely clear. By retroviral transduction of mutant AID proteins into aid-/- mouse splenic B cells, we show that 4 amino acids within the C terminus of mouse AID, when individually mutated to specific amino acids (R190K, A192K, L196S, F198S), reduce CSR about as much or more than deletion of the entire C terminal 10 amino acids. Similar to ΔAID, the substitutions reduce binding of UNG to Ig Sµ regions and some reduce binding of Msh2, both of which are important for introducing S region DNA breaks. Junctions between the IgH donor switch (S)µ and acceptor Sα regions from cells expressing ΔAID or the L196S mutant show increased microhomology compared to junctions in cells expressing wild-type AID, consistent with problems during CSR and the use of alternative end-joining, rather than non-homologous end-joining (NHEJ). Unlike deletion of the AID C terminus, 3 of the substitution mutants reduce DNA double-strand breaks (DSBs) detected within the Sµ region in splenic B cells undergoing CSR. Cells expressing these 3 substitution mutants also have greatly reduced mutations within unrearranged Sµ regions, and they decrease with time after activation. These results might be explained by increased error-free repair, but as the C terminus has been shown to be important for recruitment of NHEJ proteins, this appears unlikely. We hypothesize that Sµ DNA breaks in cells expressing these C terminus substitution mutants are poorly repaired, resulting in destruction of Sµ segments that are deaminated by these mutants. This could explain why these mutants cannot undergo CSR.
[Mh] Termos MeSH primário: Citidina Desaminase/genética
Switching de Imunoglobulina/genética
Região de Troca de Imunoglobulinas/genética
Imunoglobulinas/genética
Recombinação Genética
[Mh] Termos MeSH secundário: Substituição de Aminoácidos/genética
Animais
Linfócitos B/imunologia
Linfócitos B/metabolismo
Citidina Desaminase/imunologia
DNA/genética
Quebras de DNA de Cadeia Dupla
Reparo do DNA por Junção de Extremidades/genética
Seres Humanos
Camundongos
Camundongos Knockout
Mutação de Sentido Incorreto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Immunoglobulins); 9007-49-2 (DNA); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150813
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0134397



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