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.
Wu
Xiaosheng
X
Transplantation Biology Program and the Department of Biochemistry, Mayo Clinic, Rochester, MN 55905, USA.
Geraldes
Pedro
P
Platt
Jeffrey L
JL
Cascalho
Marilia
M
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology; D020134:Catalytic Domain / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000378:metabolism; D004247:DNA / Q000502:physiology; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D003641:Deamination; D004790:Enzyme Induction / Q000276:immunology; D006367:HeLa Cells; D006657:Histones / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion / Q000235:genetics; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1
D003564:Cytidine Deaminase; D004247:DNA; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000071857:Tumor Suppressor p53-Binding Protein 1; C092537:Ifi202b protein, mouse; C498301:TP53BP1 protein, human; C497263:PRKDC protein, human; C475961:gamma-H2AX protein, mouse