title: The ATM Kinase Restrains Joining of Both VDJ Signal and Coding Ends.
abstract: The evidence that ATM affects resolution of RAG-induced DNA double-strand breaks is profuse and unequivocal; moreover, it is clear that the RAG complex itself cooperates (in an undetermined way) with ATM to facilitate repair of these double-strand breaks by the classical nonhomologous end-joining pathway. The mechanistic basis for the cooperation between ATM and the RAG complex has not been defined, although proposed models invoke ATM and RAG2's C terminus in maintaining the RAG postcleavage complex. In this study, we show that ATM reduces the rate of both coding and signal joining in a robust episomal assay; we suggest that this is the result of increased stability of the postcleavage complex. ATM's ability to inhibit VDJ joining requires its enzymatic activity. The noncore C termini of both RAG1 and RAG2 are also required for ATM's capacity to limit signal (but not coding) joining. Moreover, potential phosphorylation targets within the C terminus of RAG2 are also required for ATM's capacity to limit signal joining. These data suggest a model whereby the RAG signal end complex is stabilized by phosphorylation of RAG2 by ATM.
authors: Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824; kmeek@msu.edu.|Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824; and.
authors: Katheryn
authors: K
authors: Meek
authors: Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.|Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824; and.
authors: Yao
authors: Y
authors: Xu
authors: Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.|Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824; and.
authors: Caleb
authors: C
authors: Bailie
authors: Department of Microbiology and Molecular Genetics, College of Human Medicine, Michigan State University, East Lansing, MI 48824.
authors: Kefei
authors: 0000-0002-3870-2812
authors: K
authors: Yu
authors: Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.|Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824; and.
authors: Jessica A
authors: JA
authors: Neal
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015322:Gene Rearrangement, B-Lymphocyte; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D021382:Protein Sorting Signals / Q000235:genetics; D055550:Protein Stability; D059767:Recombinational DNA Repair; D050441:VDJ Exons / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; C499311:RAG2 protein, human; C064658:RAG-1 protein; D064007:Ataxia Telangiectasia Mutated Proteins