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53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination

Nature Immunology volume 5, pages 481–487 (2004)Cite this article

Abstract

The mammalian protein 53BP1 is activated in many cell types in response to genotoxic stress, including DNA double-strand breaks (DSBs). We now examine potential functions for 53BP1 in the specific genomic alterations that occur in B lymphocytes. Although 53BP1 was dispensable for V(D)J recombination and somatic hypermutation (SHM), the processes by which immunoglobulin (Ig) variable region exons are assembled and mutated, it was required for Igh class-switch recombination (CSR), the recombination and deletion process by which Igh constant region genes are exchanged. When stimulated to undergo CSR, 53BP1-deficient cells exhibited no defect in CH germline transcription or AID expression, however these cells had a profound decrease in switch junctions. The current findings, in combination with the known 53BP1 functions and how it is activated, implicate the DNA damage response to DSBs in the joining phase of class-switch recombination.

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Figure 1: Bone marrow and splenic B cell development in Trp53bp1−/− mice.
Figure 2: Serum Igh isotype expression in 53BP1-deficient mice.
Figure 3: Defective Igh class switching in 53BP1-deficient B cells.
Figure 4: Induction of factors associated with CSR initiation.
Figure 5: Normal growth of activated 53BP1-deficient B cells.
Figure 6: Immunoglobulin gene SHM in Trp53bp1−/− mice.

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Acknowledgements

We thank C. Bassing for critical reading of the manuscript. The laboratories of P.B.C. and F.W.A. contributed equally to this work. Supported by the National Institutes of Health (AI3154 and CA92625 to F.W.A.), Ellison Medical Foundation (P.B.C. and F.W.A.), Cure for Lymphoma Foundation (J.P.M.) and Howard Hughes Medical Institute (F.W.A.).

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Author notes

  1. John P Manis and Julio C Morales: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, The Children's Hospital,

    John P Manis & Frederick W Alt

  2. The Department of Genetics, Harvard Medical School,

    John P Manis & Frederick W Alt

  3. The CBR Institute for Biomedical Research, Boston, Massachusetts, 02115, USA

    John P Manis & Frederick W Alt

  4. The Department of Pathology, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Jeffery L Kutok

  5. Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, 77030, Texas, USA

    Julio C Morales, Zhenfang Xia & Phillip B Carpenter

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Correspondence to John P Manis.

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Manis, J., Morales, J., Xia, Z. et al. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol 5, 481–487 (2004). https://doi.org/10.1038/ni1067

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