The Double-Edged Sword of Activation-Induced Cytidine Deaminase

• Published in: The Journal of immunology (1950) 2005-01, Vol.174 (2), p.934-941
• Main Authors: Wu, Xiaosheng, Geraldes, Pedro, Platt, Jeffrey L, Cascalho, Marilia
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - enzymology; Catalytic Domain - genetics; Catalytic Domain - immunology; Cell Line; Cell Nucleus - enzymology; Cell Survival - genetics; Cell Survival - immunology; Cells, Cultured; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - metabolism; Deamination; DNA - physiology; DNA Damage; DNA-Activated Protein Kinase; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enzyme Induction - immunology; HeLa Cells; Histones - physiology; Humans; Intracellular Fluid - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Nuclear Proteins; Peptide Fragments - genetics; Peptide Fragments - physiology; Phosphoproteins - physiology; Protein Binding - genetics; Protein Binding - immunology; Protein Structure, Tertiary - genetics; Protein Structure, Tertiary - physiology; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Sequence Deletion - genetics; Transfection; Tumor Suppressor p53-Binding Protein 1
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.2.934

Activation-induced cytidine deaminase (AID) is required for Ig class switch recombination, a process that introduces DNA double-strand breaks in B cells. We show in this study that AID associates with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promoting cell survival, presumably by resolving DNA double-strand breaks. Wild-type cells expressing AID mutants that fail to associate with DNA-PKcs or cells deficient in DNA-PKcs or 53BP1 expressing wild-type AID accumulate gammaH2AX foci, indicative of heightened DNA damage response. Thus, AID has two independent functions. AID catalyzes cytidine deamination that originates DNA double-strand breaks needed for recombination, and it promotes DNA damage response and cell survival. Our results thus resolve the paradox of how B cells undergoing DNA cytidine deamination and recombination exhibit heightened survival and suggest a mechanism for hyperIgM type II syndrome associated with AID mutants deficient in DNA-PKcs binding.