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  • 1
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    Two levels of protection for the B cell genome during somatic hypermutation (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-02-15
    Description: Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation-induced deaminase (AID) and completed by error-prone processing of the resulting uracils by mismatch and base excision repair factors. Somatic hypermutation represents a threat to genome integrity and it is not known how the B cell genome is protected from the mutagenic effects of somatic hypermutation nor how often these protective mechanisms fail. Here we show, by extensive sequencing of murine B cell genes, that the genome is protected by two distinct mechanisms: selective targeting of AID and gene-specific, high-fidelity repair of AID-generated uracils. Numerous genes linked to B cell tumorigenesis, including Myc, Pim1, Pax5, Ocab (also called Pou2af1), H2afx, Rhoh and Ebf1, are deaminated by AID but escape acquisition of most mutations through the combined action of mismatch and base excision repair. However, approximately 25% of expressed genes analysed were not fully protected by either mechanism and accumulated mutations in germinal centre B cells. Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Man -- Duke, Jamie L -- Richter, Daniel J -- Vinuesa, Carola G -- Goodnow, Christopher C -- Kleinstein, Steven H -- Schatz, David G -- England -- Nature. 2008 Feb 14;451(7180):841-5. doi: 10.1038/nature06547.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18273020" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Diversity/*genetics ; B-Lymphocytes/enzymology/*metabolism ; Cytidine Deaminase/deficiency/genetics/*metabolism ; *DNA Repair ; Genome/*genetics ; Genomic Instability/genetics ; Mice ; MutS Homolog 2 Protein/deficiency/genetics ; Mutagenesis/*genetics ; Uracil-DNA Glycosidase/deficiency/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination (1990)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1990-06-22
    Description: The vast repertoire of immunoglobulins and T cell receptors is generated, in part, by V(D)J recombination, a series of genomic rearrangements that occur specifically in developing lymphocytes. The recombination activating gene, RAG-1, which is a gene expressed exclusively in maturing lymphoid cells, was previously isolated. RAG-1 inefficiently induced V(D)J recombinase activity when transfected into fibroblasts, but cotransfection with an adjacent gene, RAG-2, has resulted in at least a 1000-fold increase in the frequency of recombination. The 2.1-kilobase RAG-2 complementary DNA encodes a putative protein of 527 amino acids whose sequence is unrelated to that of RAG-1. Like RAG-1, RAG-2 is conserved between species that carry out V(D)J recombination, and its expression pattern correlates precisely with that of V(D)J recombinase activity. In addition to being located just 8 kilobases apart, these convergently transcribed genes are unusual in that most, if not all, of their coding and 3' untranslated sequences are contained in single exons. RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oettinger, M A -- Schatz, D G -- Gorka, C -- Baltimore, D -- GM39458/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1990 Jun 22;248(4962):1517-23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2360047" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Biological Evolution ; Cattle ; Cell Line ; Chickens ; Cricetinae ; DNA/*genetics ; DNA Nucleotidyltransferases/*genetics ; *DNA-Binding Proteins ; Dogs ; Female ; *Gene Rearrangement, B-Lymphocyte ; *Gene Rearrangement, T-Lymphocyte ; *Homeodomain Proteins ; Humans ; Male ; Mice ; Molecular Sequence Data ; *Multigene Family ; Nuclear Proteins ; Nucleic Acid Hybridization ; Opossums ; Proteins/*genetics ; Rabbits ; Recombination, Genetic/*genetics ; Restriction Mapping ; Transfection ; Turtles ; VDJ Recombinases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-08-16
    Description: The expression of the V(D)J [variable (diversity) joining elements] recombination activating genes, RAG-1 and RAG-2, has been examined during T cell development in the thymus. In situ hybridization to intact thymus and RNA blot analysis of isolated thymic subpopulations separated on the basis of T cell receptor (TCR) expression demonstrated that both TCR- and TCR+ cortical thymocytes express RAG-1 and RAG-2 messenger RNA's. Within the TCR+ population, RAG expression was observed in immature CD4+CD8+ (double positive) cells, but not in the more mature CD4+CD8- or CD4-CD8+ (single positive) subpopulations. Thus, although cortical thymocytes that bear TCR on their surface continue to express RAG-1 and RAG-2, it appears that the expression of both genes is normally terminated during subsequent thymic maturation. Since thymocyte maturation in vivo is thought to be regulated through the interaction of the TCR complex with self major histocompatibility complex (MHC) antigens, these data suggest that signals transduced by the TCR complex might result in the termination of RAG expression. Consistent with this hypothesis, thymocyte TCR cross-linking in vitro led to rapid termination of RAG-1 and RAG-2 expression, whereas cross-linking of other T cell surface antigens such as CD4, CD8, or HLA class I had no effect.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turka, L A -- Schatz, D G -- Oettinger, M A -- Chun, J J -- Gorka, C -- Lee, K -- McCormack, W T -- Thompson, C B -- DK-01899/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1991 Aug 16;253(5021):778-81.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, University of Michigan, Ann Arbor 48109.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1831564" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/physiology ; Antigens, CD3 ; Antigens, Differentiation, T-Lymphocyte/physiology ; Cell Differentiation ; Cell Survival ; DNA Nucleotidyltransferases/*genetics ; *DNA-Binding Proteins ; Gene Expression ; *Gene Rearrangement, T-Lymphocyte ; *Homeodomain Proteins ; Humans ; Mice ; Nuclear Proteins ; Nucleic Acid Hybridization ; Proteins/*genetics ; RNA, Messenger/genetics ; Receptor Aggregation ; Receptors, Antigen, T-Cell/*physiology ; Receptors, Interleukin-2/genetics ; T-Lymphocyte Subsets/enzymology/*physiology ; Thymus Gland/cytology/*enzymology ; VDJ Recombinases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Immunology. UNGstoppable switching (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-08-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Unniraman, Shyam -- Fugmann, Sebastian D -- Schatz, David G -- New York, N.Y. -- Science. 2004 Aug 20;305(5687):1113-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. shyam.unniraman@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15326342" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/enzymology/immunology/*physiology ; Cytidine Deaminase/metabolism ; DNA/metabolism ; DNA Glycosylases/antagonists & inhibitors/*metabolism ; DNA Repair ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Genes, Immunoglobulin ; *Immunoglobulin Class Switching ; Mice ; Models, Genetic ; Models, Immunological ; Mutation ; Recombination, Genetic ; Somatic Hypermutation, Immunoglobulin ; Uracil-DNA Glycosidase
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Immunology. One AID to unite them all (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-02-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fugmann, Sebastian D -- Schatz, David G -- New York, N.Y. -- Science. 2002 Feb 15;295(5558):1244-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Section of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11847327" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Diversity ; Apolipoprotein B-48 ; Apolipoproteins B/chemistry/metabolism ; B-Lymphocytes/enzymology/*immunology ; Catalytic Domain ; Chickens ; Cytidine Deaminase/chemistry/*genetics/*metabolism ; DNA/metabolism ; DNA Repair ; *Gene Conversion ; *Genes, Immunoglobulin ; Immunoglobulin Class Switching ; RNA/metabolism ; RNA Editing ; Recombination, Genetic ; Somatic Hypermutation, Immunoglobulin
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-08-13
    Description: Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis. There is growing evidence that cohesin also forms long-range chromosomal cis-interactions and may regulate gene expression in association with CTCF, mediator or tissue-specific transcription factors. Human cohesinopathies such as Cornelia de Lange syndrome are thought to result from impaired non-canonical cohesin functions, but a clear distinction between the cell-division-related and cell-division-independent functions of cohesion--as exemplified in Drosophila--has not been demonstrated in vertebrate systems. To address this, here we deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor (TCR) alpha locus (Tcra). Rad21-deficient thymocytes had a normal lifespan and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesion-binding sites flank the TEA promoter and the Ealpha enhancer, and demarcate Tcra from interspersed Tcrd elements and neighbouring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery and Tcra rearrangement. Provision of pre-rearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. These findings firmly establish a cell-division-independent role for cohesin in Tcra locus rearrangement and provide a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179485/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179485/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seitan, Vlad C -- Hao, Bingtao -- Tachibana-Konwalski, Kikue -- Lavagnolli, Thais -- Mira-Bontenbal, Hegias -- Brown, Karen E -- Teng, Grace -- Carroll, Tom -- Terry, Anna -- Horan, Katie -- Marks, Hendrik -- Adams, David J -- Schatz, David G -- Aragon, Luis -- Fisher, Amanda G -- Krangel, Michael S -- Nasmyth, Kim -- Merkenschlager, Matthias -- 13031/Cancer Research UK/United Kingdom -- MC_U120027516/Medical Research Council/United Kingdom -- MC_U120081295/Medical Research Council/United Kingdom -- R37 AI032524/AI/NIAID NIH HHS/ -- R37 AI032524-20/AI/NIAID NIH HHS/ -- R37 GM041052/GM/NIGMS NIH HHS/ -- R37 GM041052-22/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Aug 10;476(7361):467-71. doi: 10.1038/nature10312.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21832993" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle Proteins/genetics/*metabolism ; *Cell Differentiation ; Chromosomal Proteins, Non-Histone/deficiency/genetics/*metabolism ; Gene Expression Regulation ; *Gene Rearrangement, T-Lymphocyte/genetics ; Genes, RAG-1/genetics ; Mice ; Nuclear Proteins/deficiency/genetics/*metabolism ; Phosphoproteins/deficiency/genetics/*metabolism ; Receptors, Antigen, T-Cell, alpha-beta/*genetics/*metabolism ; Recombinases/metabolism ; Thymus Gland/*cytology/metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 7
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    Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-12-20
    Description: The products of the Rag1 and Rag2 genes drive genomic V(D)J rearrangements that assemble functional immunoglobulin and T cell antigen receptor genes. Expression of the Rag genes has been thought to be limited to developmentally immature lymphocyte populations that in normal adult animals are primarily restricted to the bone marrow and thymus. Abundant RAG1 and RAG2 protein and messenger RNA was detected in the activated B cells that populate murine splenic and Peyer's patch germinal centers. Germinal center B cells thus share fundamental characteristics of immature lymphocytes, raising the possibility that antigen-dependent secondary V(D)J rearrangements modify the peripheral antibody repertoire.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, S -- Zheng, B -- Schatz, D G -- Spanopoulou, E -- Kelsoe, G -- AG10207/AG/NIA NIH HHS/ -- AI24335/AI/NIAID NIH HHS/ -- AI32524/AI/NIAID NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1996 Dec 20;274(5295):2094-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8953043" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/immunology/*metabolism ; DNA Nucleotidyltransferases/metabolism ; *DNA-Binding Proteins ; Female ; *Gene Expression ; Gene Rearrangement ; Genes, Immunoglobulin ; *Genes, RAG-1 ; Germinal Center/*cytology/immunology ; *Homeodomain Proteins ; Immunization ; Immunoglobulin Class Switching ; *Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Polymerase Chain Reaction ; Protein Biosynthesis ; Proteins/*genetics ; VDJ Recombinases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    Strand-biased spreading of mutations during somatic hypermutation (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-09-01
    Description: Somatic hypermutation (SHM) is a major means by which diversity is achieved in antibody genes, and it is initiated by the deamination of cytosines to uracils in DNA by activation-induced deaminase (AID). However, the process that leads from these initiating deamination events to mutations at other residues remains poorly understood. We demonstrate that a single cytosine on the top (nontemplate) strand is sufficient to recruit AID and lead to mutations of upstream and downstream A/T residues. In contrast, the targeting of cytosines on the bottom strand by AID does not lead to substantial mutation of neighboring residues. This strand asymmetry is eliminated in mice deficient in mismatch repair, indicating that the error-prone mismatch repair machinery preferentially targets top-strand uracils in a way that promotes SHM during the antibody response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Unniraman, Shyam -- Schatz, David G -- New York, N.Y. -- Science. 2007 Aug 31;317(5842):1227-30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17761884" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/metabolism ; Animals ; B-Lymphocytes ; Base Sequence ; Cytidine Deaminase/*metabolism ; Cytosine/*metabolism ; DNA Mismatch Repair ; Deamination ; *Genes, Immunoglobulin ; Immunoglobulin Variable Region/genetics ; Immunoglobulin kappa-Chains/genetics ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; *Somatic Hypermutation, Immunoglobulin ; Thymine/metabolism ; Transgenes ; Uracil/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
    Electronic Resource
    Electronic Resource
    V(D)J Recombination: Molecular Biology and Regulation (1992)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 10 (1992), S. 359-383 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.10.040192.002043
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  • 10
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    Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination (2005)
    National Academy of Sciences
    Details
    Publication Date: 2005-09-02
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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