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  • 1
    Publication Date: 2002-04-06
    Description: Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721576/" 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/PMC4721576/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Celeste, Arkady -- Petersen, Simone -- Romanienko, Peter J -- Fernandez-Capetillo, Oscar -- Chen, Hua Tang -- Sedelnikova, Olga A -- Reina-San-Martin, Bernardo -- Coppola, Vincenzo -- Meffre, Eric -- Difilippantonio, Michael J -- Redon, Christophe -- Pilch, Duane R -- Olaru, Alexandru -- Eckhaus, Michael -- Camerini-Otero, R Daniel -- Tessarollo, Lino -- Livak, Ferenc -- Manova, Katia -- Bonner, William M -- Nussenzweig, Michel C -- Nussenzweig, Andre -- Z99 CA999999/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2002 May 3;296(5569):922-7. Epub 2002 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11934988" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; B-Lymphocytes/immunology/physiology ; Base Sequence ; Cell Aging ; Cell Cycle ; Cells, Cultured ; *Chromosome Aberrations ; DNA Damage ; *DNA Repair ; Female ; Gene Targeting ; Histones/chemistry/*genetics/*physiology ; Immunoglobulin Class Switching ; Infertility, Male/genetics/physiopathology ; Lymphocyte Count ; Male ; Meiosis ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Mutation ; Phosphorylation ; *Recombination, Genetic ; Spermatocytes/physiology ; T-Lymphocytes/immunology/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2008-10-22
    Description: Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596817/" 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/PMC3596817/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Difilippantonio, Simone -- Gapud, Eric -- Wong, Nancy -- Huang, Ching-Yu -- Mahowald, Grace -- Chen, Hua Tang -- Kruhlak, Michael J -- Callen, Elsa -- Livak, Ferenc -- Nussenzweig, Michel C -- Sleckman, Barry P -- Nussenzweig, Andre -- R01AI074953/AI/NIAID NIH HHS/ -- Z01 BC010283-10/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 27;456(7221):529-33. doi: 10.1038/nature07476. Epub 2008 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18931658" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Chromosomal Proteins, Non-Histone ; DNA/genetics/*metabolism ; DNA Breaks ; DNA-Binding Proteins ; Gene Rearrangement, T-Lymphocyte/*genetics ; Genes, T-Cell Receptor alpha/genetics ; Genomic Instability ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism ; Lymphopenia/genetics/pathology ; Mice ; Models, Genetic ; Receptors, Antigen, T-Cell/genetics/metabolism ; *Recombination, Genetic ; Sequence Homology ; T-Lymphocytes/cytology/metabolism ; Thymus Gland/cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2000-12-09
    Description: Genetic disorders affecting cellular responses to DNA damage are characterized by high rates of translocations involving antigen receptor loci and increased susceptibility to lymphoid malignancies. We report that the Nijmegen breakage syndrome protein (NBS1) and histone gamma-H2AX, which associate with irradiation-induced DNA double-strand breaks (DSBs), are also found at sites of VDJ (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T cell receptor alpha locus in response to recombination activating gene (RAG) protein-mediated VDJ cleavage. Our results suggest that surveillance of T cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721589/" 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/PMC4721589/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, H T -- Bhandoola, A -- Difilippantonio, M J -- Zhu, J -- Brown, M J -- Tai, X -- Rogakou, E P -- Brotz, T M -- Bonner, W M -- Ried, T -- Nussenzweig, A -- Z99 CA999999/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2000 Dec 8;290(5498):1962-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11110662" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Nucleus/metabolism ; DNA Damage ; DNA-Binding Proteins/metabolism ; Fluorescent Antibody Technique ; *Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor ; *Genes, T-Cell Receptor alpha ; Histones/*metabolism ; Homeodomain Proteins/metabolism ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Phosphorylation ; *Recombination, Genetic ; T-Lymphocytes/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1997-10-10
    Description: The clonal selection theory states that B lymphocytes producing high-affinity immunoglobulins are selected from a pool of cells undergoing antibody gene mutation. Somatic hypermutation is a well-documented mechanism for achieving diversification of immune responses in mature B cells. Antibody genes were also found to be modified in such cells in germinal centers by recombination of the variable (V), diversity (D), and joining (J) segments. The ability to alter immunoglobulin expression by V(D)J recombination in the selective environment of the germinal center may be an additional mechanism for inactivation or diversification of immune responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Papavasiliou, F -- Casellas, R -- Suh, H -- Qin, X F -- Besmer, E -- Pelanda, R -- Nemazee, D -- Rajewsky, K -- Nussenzweig, M C -- AI33890/AI/NIAID NIH HHS/ -- R01 AI033608/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 1997 Oct 10;278(5336):298-301.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9323210" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antibody Diversity ; B-Lymphocytes/*immunology ; Cells, Cultured ; DNA Nucleotidyltransferases/genetics/metabolism ; DNA-Binding Proteins/genetics ; Gene Expression ; *Gene Rearrangement, B-Lymphocyte ; Genes, Immunoglobulin ; Genes, RAG-1 ; Germinal Center/cytology/immunology ; Immunoglobulin Joining Region/*genetics ; Immunoglobulin M/biosynthesis/genetics ; Immunoglobulin Variable Region/*genetics ; Lymphocyte Activation ; Mice ; *Recombination, Genetic ; VDJ Recombinases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1996-04-19
    Description: Many of the cell fate decisions in precursor B cells and more mature B cells are controlled by membrane immunoglobulin (Ig)M heavy chain (mu) and the Ig alpha-Ig beta signal transducers. The role of Ig beta in regulating early B cell development was examined in mice that lack Ig beta (Ig beta-/-). These mice had a complete block in B cell development at the immature CD43+B220+ stage. Immunoglobulin heavy chain diversity (DH) and joining (JH) segments rearranged, but variable (VH) to DJH recombination and immunoglobulin messenger RNA expression were compromised. These experiments define an unexpected, early requirement for Ig(beta) to produce B cells that can complete VDJH recombination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, S -- Nussenzweig, M C -- New York, N.Y. -- Science. 1996 Apr 19;272(5260):411-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Rockefeller University, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8602530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/genetics/*physiology ; Antigens, CD79 ; B-Lymphocytes/cytology/*immunology ; Gene Expression ; *Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Gene Targeting ; Genes, Immunoglobulin ; Immunoglobulin Heavy Chains/*genetics ; Immunoglobulin Joining Region/genetics ; Immunoglobulin Light Chains/*genetics ; Immunoglobulin Variable Region/genetics ; Immunoglobulin mu-Chains/biosynthesis/genetics/physiology ; Lymph Nodes ; Mice ; Mice, Inbred C57BL ; Mutation ; RNA, Messenger/genetics ; Receptors, Antigen, B-Cell/physiology ; *Recombination, Genetic ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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