The double-edged sword of activation-induced cytidine deaminase.

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.
Mesh Terms:
Animals, B-Lymphocyte Subsets, Catalytic Domain, Cell Line, Cell Nucleus, Cell Survival, Cells, Cultured, Cytidine Deaminase, DNA, DNA Damage, DNA-Activated Protein Kinase, DNA-Binding Proteins, Deamination, Enzyme Induction, Hela Cells, Histones, Humans, Intracellular Fluid, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Nuclear Proteins, Peptide Fragments, Phosphoproteins, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Sequence Deletion, Transfection
J. Immunol.
Date: Jan. 15, 2005
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