1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360, USA
2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
3. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
4. Laboratory of Molecular Immunology, The Rockefeller University and Howard Hughes Medical Institute, New York, New York 10021, USA
5. These authors contributed equally to this work.

Correspondence to: André Nussenzweig^1,5 Correspondence and requests for materials should be addressed to A.N. (Email: andre_nussenzweig@nih.gov).

Abstract

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^{1, 2}. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination^{3, 4}. 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 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.

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