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AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching

Author

Listed:
  • Simone Petersen

    (Experimental Immunology Branch, National Cancer Institute, National Institutes of Health)

  • Rafael Casellas

    (Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute)

  • Bernardo Reina-San-Martin

    (Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute)

  • Hua Tang Chen

    (Experimental Immunology Branch, National Cancer Institute, National Institutes of Health)

  • Michael J. Difilippantonio

    (Genetics Branch, National Cancer Institute, National Institutes of Health)

  • Patrick C. Wilson

    (Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute)

  • Leif Hanitsch

    (Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute)

  • Arkady Celeste

    (Experimental Immunology Branch, National Cancer Institute, National Institutes of Health)

  • Masamichi Muramatsu

    (Graduate School of Medicine, Kyoto University)

  • Duane R. Pilch

    (Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health)

  • Christophe Redon

    (Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health)

  • Thomas Ried

    (Genetics Branch, National Cancer Institute, National Institutes of Health)

  • William M. Bonner

    (Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health)

  • Tasuku Honjo

    (Graduate School of Medicine, Kyoto University)

  • Michel C. Nussenzweig

    (Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute)

  • André Nussenzweig

    (Experimental Immunology Branch, National Cancer Institute, National Institutes of Health)

Abstract

Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region (Ch) gene with another. This enables a single variable (V) region gene to be used in conjunction with different downstream Ch genes, each having a unique biological activity. The molecular mechanisms that mediate CSR have not been defined, but activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme, is required for this reaction1. Here we report that the Nijmegen breakage syndrome protein (Nbs1) and phosphorylated H2A histone family member X (γ-H2AX, also known as γ-H2afx), which facilitate DNA double-strand break (DSB) repair2,3,4, form nuclear foci at the Ch region in the G1 phase of the cell cycle in cells undergoing CSR, and that switching is impaired in H2AX-/- mice. Localization of Nbs1 and γ-H2AX to the Igh locus during CSR is dependent on AID. In addition, AID is required for induction of switch region (Sµ)-specific DNA lesions that precede CSR. These results place AID function upstream of the DNA modifications that initiate CSR.

Suggested Citation

  • Simone Petersen & Rafael Casellas & Bernardo Reina-San-Martin & Hua Tang Chen & Michael J. Difilippantonio & Patrick C. Wilson & Leif Hanitsch & Arkady Celeste & Masamichi Muramatsu & Duane R. Pilch &, 2001. "AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching," Nature, Nature, vol. 414(6864), pages 660-665, December.
    • Handle: RePEc:nat:nature:v:414:y:2001:i:6864:d:10.1038_414660a
    DOI: 10.1038/414660a
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