Abstract
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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
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
-
DNA / physiology
-
DNA Damage
-
DNA-Activated Protein Kinase
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / physiology
-
Deamination
-
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 Serine-Threonine Kinases / metabolism
-
Protein Serine-Threonine Kinases / physiology
-
Protein Structure, Tertiary / genetics
-
Protein Structure, Tertiary / physiology
-
Sequence Deletion / genetics
-
Transfection
-
Tumor Suppressor p53-Binding Protein 1
Substances
-
DNA-Binding Proteins
-
H2AX protein, mouse
-
Histones
-
Ifi202b protein, mouse
-
Intracellular Signaling Peptides and Proteins
-
Nuclear Proteins
-
Peptide Fragments
-
Phosphoproteins
-
TP53BP1 protein, human
-
Tumor Suppressor p53-Binding Protein 1
-
DNA
-
DNA-Activated Protein Kinase
-
PRKDC protein, human
-
Protein Serine-Threonine Kinases
-
Cytidine Deaminase