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  1. Article: Mutational analyses of lymphocyte differentiation.

    Alt, F W

    Harvey lectures

    1992  Volume 88, Page(s) 97–114

    Abstract: The site-specific recombination mechanism responsible for the assembly of antigen receptor variable region genes is only employed in lymphocyte development. Gene-targeted and other types of mutational analyses have implicated at least seven distinct gene ...

    Abstract The site-specific recombination mechanism responsible for the assembly of antigen receptor variable region genes is only employed in lymphocyte development. Gene-targeted and other types of mutational analyses have implicated at least seven distinct gene products, some lymphoid-specific and others more generally expressed, as involved in aspects of this process. Mutation of the lymphocyte-specific activities required for VDJ recombination or mutation of the target gene segments of this process have created B and/or T cell-deficient mouse models that have provided new insights into the regulation of the VDJ recombination reaction and into how the successful achievement of this reaction at various loci helps lead lymphocytes through their early developmental program A second type of B lymphocyte-specific recombination process is involved in heavy-chain class switching; gene-targeted mutation approaches also have provided new insights into the cis-acting elements that target of this reaction to particular CH genes.
    MeSH term(s) Animals ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Gene Rearrangement, B-Lymphocyte ; Gene Rearrangement, T-Lymphocyte ; Humans ; Immunoglobulin Class Switching/genetics ; Lymphocytes/cytology ; Lymphocytes/immunology ; Mice ; Mutation ; Recombination, Genetic
    Language English
    Publishing date 1992
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 214075-5
    ISSN 0073-0874
    ISSN 0073-0874
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: DNA double strand break repair and chromosomal translocation: lessons from animal models.

    Ferguson, D O / Alt, F W

    Oncogene

    2001  Volume 20, Issue 40, Page(s) 5572–5579

    Abstract: The maintenance of genomic stability is one of the most important defenses against neoplastic transformation. This objective must be accomplished despite a constant barrage of spontaneous DNA double strand breaks. These dangerous lesions are corrected by ...

    Abstract The maintenance of genomic stability is one of the most important defenses against neoplastic transformation. This objective must be accomplished despite a constant barrage of spontaneous DNA double strand breaks. These dangerous lesions are corrected by two primary pathways of double strand break repair; non homologous end joining and homologous recombination. Recent studies employing mouse models have shown that absence of either pathway leads to genomic instability, including potentially oncogenic translocations. Because translocations involve the union of different chromosomes, cellular machinery must exist that creates these structures in the context of unrepaired double strand breaks. Evidence is mounting that the pathways of double strand break repair that are so important for survival may themselves be the culprits that generate potentially fatal translocations. Evidence and models for the dual roles of double strand break repair in both preventing, and generating, oncogenic karyotypic changes are discussed.
    MeSH term(s) Animals ; Chromosomes/ultrastructure ; DNA Damage ; DNA Repair ; Mice ; Models, Genetic ; Recombination, Genetic ; Translocation, Genetic
    Language English
    Publishing date 2001-09-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/sj.onc.1204767
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  3. Article: Transcription-induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro.

    Tian, M / Alt, F W

    The Journal of biological chemistry

    2000  Volume 275, Issue 31, Page(s) 24163–24172

    Abstract: Immunoglobulin (Ig) heavy chain class switch recombination (CSR) mediates isotype switching during B cell development. CSR occurs between switch (S) regions that precede each Ig heavy chain constant region gene. Various studies have demonstrated that ... ...

    Abstract Immunoglobulin (Ig) heavy chain class switch recombination (CSR) mediates isotype switching during B cell development. CSR occurs between switch (S) regions that precede each Ig heavy chain constant region gene. Various studies have demonstrated that transcription plays an essential role in CSR in vivo. In this study, we show that in vitro transcription of S regions in their physiological orientation induces the formation of stable R loops. Furthermore, we show that the nucleotide excision repair nucleases XPF-ERCC1 and XPG can cleave the R loops formed in the S regions. Based on these findings, we propose that CSR is initiated via a mechanism that involves transcription-dependent S region cleavage by DNA structure-specific endonucleases that function in general DNA repair processes. Such a mechanism also may underlie transcription-dependent mutagenic processes such as somatic hypermutation, and contribute to genomic instability in general.
    MeSH term(s) DNA Repair ; DNA-Binding Proteins/metabolism ; Endonucleases/metabolism ; Immunoglobulin Switch Region/genetics ; Models, Genetic ; Nuclear Proteins ; Nucleic Acid Conformation ; Proteins/metabolism ; Recombination, Genetic ; Substrate Specificity ; Transcription Factors ; Transcription, Genetic
    Chemical Substances DNA excision repair protein ERCC-5 ; DNA-Binding Proteins ; Nuclear Proteins ; Proteins ; Transcription Factors ; xeroderma pigmentosum group F protein ; Endonucleases (EC 3.1.-)
    Language English
    Publishing date 2000-08-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M003343200
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  4. Article: RNA editing meets DNA shuffling.

    Tian, M / Alt, F W

    Nature

    2000  Volume 407, Issue 6800, Page(s) 31, 33

    MeSH term(s) APOBEC-1 Deaminase ; Animals ; Cytidine Deaminase/metabolism ; Gene Rearrangement, B-Lymphocyte ; Immunologic Deficiency Syndromes/genetics ; Immunologic Deficiency Syndromes/immunology ; Mice ; RNA Editing
    Chemical Substances AICDA (activation-induced cytidine deaminase) (EC 3.5.4.-) ; APOBEC-1 Deaminase (EC 3.5.4.36) ; Apobec1 protein, mouse (EC 3.5.4.36) ; Cytidine Deaminase (EC 3.5.4.5)
    Language English
    Publishing date 2000-09-07
    Publishing country England
    Document type News
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/35024189
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  5. Article ; Online: SIRT6 in DNA repair, metabolism and ageing.

    Lombard, D B / Schwer, B / Alt, F W / Mostoslavsky, R

    Journal of internal medicine

    2008  Volume 263, Issue 2, Page(s) 128–141

    Abstract: Ageing, or increased mortality with time, coupled with physiologic decline, is a nearly universal yet poorly understood biological phenomenon. Studies in model organisms suggest that two conserved pathways modulate longevity: DNA damage repair and ... ...

    Abstract Ageing, or increased mortality with time, coupled with physiologic decline, is a nearly universal yet poorly understood biological phenomenon. Studies in model organisms suggest that two conserved pathways modulate longevity: DNA damage repair and Insulin/Igf1-like signalling. In addition, homologs of yeast Sir2--the sirtuins--regulate lifespan in diverse organisms. Here, we focus on one particular sirtuin, SIRT6. Mice lacking SIRT6 develop a degenerative disorder that in some respects mimics models of accelerated ageing [Cell (2006) 124:315]. We discuss how sirtuins in general and SIRT6 specifically relate to other evolutionarily conserved pathways affecting ageing, and how SIRT6 might function to ensure organismal homeostasis and normal lifespan.
    MeSH term(s) Aging/metabolism ; Animals ; DNA Repair/physiology ; Longevity ; Mice ; Mice, Knockout ; Models, Biological ; Phenotype ; Sirtuins/metabolism
    Chemical Substances Sirtuins (EC 3.5.1.-)
    Language English
    Publishing date 2008-01-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 96274-0
    ISSN 1365-2796 ; 0954-6820
    ISSN (online) 1365-2796
    ISSN 0954-6820
    DOI 10.1111/j.1365-2796.2007.01902.x
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  6. Article: Antibody diversity. New mechanism revealed.

    Alt, F W

    Nature

    1986  Volume 322, Issue 6082, Page(s) 772–773

    MeSH term(s) Antibody Diversity ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics
    Chemical Substances Immunoglobulin Heavy Chains ; Immunoglobulin Variable Region
    Language English
    Publishing date 1986-08
    Publishing country England
    Document type News
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/322772a0
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  7. Article: Regulation of immunoglobulin light chain isotype expression.

    Gorman, J R / Alt, F W

    Advances in immunology

    1998  Volume 69, Page(s) 113–181

    MeSH term(s) Alleles ; Animals ; Antibodies/immunology ; Gene Expression Regulation ; Gene Rearrangement ; Genes, Immunoglobulin ; Humans ; Immunoglobulin Isotypes/genetics ; Immunoglobulin Light Chains/genetics ; Immunoglobulin kappa-Chains/genetics
    Chemical Substances Antibodies ; Immunoglobulin Isotypes ; Immunoglobulin Light Chains ; Immunoglobulin kappa-Chains
    Language English
    Publishing date 1998
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80226-8
    ISSN 1557-8445 ; 0065-2776
    ISSN (online) 1557-8445
    ISSN 0065-2776
    DOI 10.1016/s0065-2776(08)60607-0
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  8. Article: V(D)J recombination. From RAGs to stitches.

    Weaver, D T / Alt, F W

    Nature

    1997  Volume 388, Issue 6641, Page(s) 428–429

    MeSH term(s) Antigens, Nuclear ; DNA ; DNA Helicases ; DNA Ligase ATP ; DNA Ligases/physiology ; DNA, Fungal/genetics ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/physiology ; Homeodomain Proteins ; Immunoglobulin J-Chains/genetics ; Immunoglobulin Variable Region/genetics ; Ku Autoantigen ; Nuclear Proteins/physiology ; Protein-Serine-Threonine Kinases/physiology ; Recombination, Genetic ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins
    Chemical Substances Antigens, Nuclear ; DNA, Fungal ; DNA-Binding Proteins ; Homeodomain Proteins ; Immunoglobulin J-Chains ; Immunoglobulin Variable Region ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; V(D)J recombination activating protein 2 ; XRCC4 protein, human ; high affinity DNA-binding factor, S cerevisiae ; RAG-1 protein (128559-51-3) ; DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; DNA Helicases (EC 3.6.4.-) ; XRCC5 protein, human (EC 3.6.4.12) ; Xrcc6 protein, human (EC 3.6.4.12) ; Ku Autoantigen (EC 4.2.99.-) ; DNA Ligases (EC 6.5.1.-) ; DNA Ligase ATP (EC 6.5.1.1)
    Language English
    Publishing date 1997-07-31
    Publishing country England
    Document type News ; Comment
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/41225
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  9. Article: Exclusive immunoglobulin genes.

    Alt, F W

    Nature

    1984  Volume 312, Issue 5994, Page(s) 502–503

    MeSH term(s) Alleles ; Animals ; Gene Expression Regulation ; Immunoglobulins/genetics ; Mice
    Chemical Substances Immunoglobulins
    Language English
    Publishing date 1984-12
    Publishing country England
    Document type News
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/312502a0
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  10. Article: Identification of the XRCC4 gene: complementation of the DSBR and V(D)J recombination defects of XR-1 cells.

    Li, Z / Alt, F W

    Current topics in microbiology and immunology

    1996  Volume 217, Page(s) 143–150

    MeSH term(s) Animals ; CHO Cells ; Cloning, Molecular ; Cricetinae ; DNA Repair/genetics ; DNA-Binding Proteins/genetics ; Genetic Complementation Test ; Humans ; Radiation Tolerance/genetics ; Receptors, Antigen/genetics ; Recombination, Genetic ; X-Rays
    Chemical Substances DNA-Binding Proteins ; Receptors, Antigen ; XRCC4 protein, human
    Language English
    Publishing date 1996
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
    ISSN 0070-217X
    ISSN 0070-217X
    DOI 10.1007/978-3-642-50140-1_10
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