Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining

J Immunol. 2008 Aug 15;181(4):2620-5. doi: 10.4049/jimmunol.181.4.2620.

Abstract

During lymphocyte Ag receptor gene assembly, DNA cleavage by the Rag proteins generates pairs of coding and signal ends that are normally joined into coding joints and signal joints, respectively, by the classical nonhomologous end-joining (NHEJ) pathway of DNA double strand break repair. Coding and signal ends can also be aberrantly joined to each other, generating hybrid joints, through NHEJ or through NHEJ-independent pathways, such as Rag-mediated transposition. Hybrid joints do not participate in the formation of functional Ag receptor genes and can alter the configuration of Ag receptor loci in ways that limit subsequent productive rearrangements. The formation of these nonfunctional hybrid joints occurs rarely in wild type lymphocytes, demonstrating that mechanisms exist to limit both the NHEJ-dependent and the NHEJ-independent joining of a signal end to a coding end. In contrast to wild-type cells, hybrid joint formation occurs at high levels in ataxia telangiectasia mutated (Atm)-deficient lymphocytes, suggesting that Atm functions to limit the formation of these aberrant joints. In this study, we show that hybrid joint formation in Atm-deficient cells requires the NHEJ proteins Artemis, DNA-PKcs, and Ku70, demonstrating that Atm functions primarily by modulating the NHEJ-dependent, and not the NHEJ-independent, joining of coding ends to signal ends.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia / enzymology
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / metabolism*
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / physiology
  • Cell Line
  • Cell Line, Transformed
  • Cells, Cultured
  • DNA Breaks, Double-Stranded*
  • DNA Damage*
  • DNA Repair*
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Gene Rearrangement, B-Lymphocyte / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / physiology
  • Recombination, Genetic
  • Stem Cells / metabolism
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases