Essential and perilous: V(D)J recombination and DNA damage checkpoints in lymphocyte precursors.
V(D)J recombination generates a diverse array of antigen-binding specificities, but breakage and re-joining of DNA segments have grave implications for the maintenance of genomic stability and oncogenic risk. Exposure of eukaryotic cells to genotoxic agents activates a DNA damage checkpoint that induces cell-cycle arrest and DNA repair, or apoptosis. We discuss several lines of evidence implicating DNA-dependent protein kinase (DNA-PK), and the gene mutated in ataxia telangiectasia (ATM), two mammalian homologues of yeast DNA damage-checkpoint genes, in regulating the response to intrinsic DNA damage that occurs during V(D)J recombination.
Danska
J S
JS
Hospital for Sick Children Research Institute, Toronto, ON, Canada.
Guidos
C J
CJ
D000595:Amino Acid Sequence; D000818:Animals; D034961:Antigens, Nuclear; D001260:Ataxia Telangiectasia / Q000235:genetics; D002453:Cell Cycle; D004249:DNA Damage; D004265:DNA Helicases; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D000072200:Ku Autoantigen; D008214:Lymphocytes / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011946:Receptors, Antigen / Q000235:genetics*; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D016511:Severe Combined Immunodeficiency / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011946:Receptors, Antigen; D029701:Saccharomyces cerevisiae Proteins; C081647:high affinity DNA-binding factor, S cerevisiae; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen