RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci

Nat Immunol. 2009 Jun;10(6):655-64. doi: 10.1038/ni.1735.

Abstract

Coordinated recombination of homologous antigen receptor loci is thought to be important for allelic exclusion. Here we show that homologous immunoglobulin alleles pair in a stage-specific way that mirrors the recombination patterns of these loci. The frequency of homologous immunoglobulin pairing was much lower in the absence of the RAG-1-RAG-2 recombinase and was restored in Rag1-/- developing B cells with a transgene expressing a RAG-1 active-site mutant that supported DNA binding but not cleavage. The introduction of DNA breaks on one immunoglobulin allele induced ATM-dependent repositioning of the other allele to pericentromeric heterochromatin. ATM activated by the cleaved allele acts in trans on the uncleaved allele to prevent biallelic recombination and chromosome breaks or translocations.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • B-Lymphocytes / metabolism
  • Cell Cycle Proteins / genetics*
  • Cells, Cultured
  • DNA Breaks
  • DNA-Binding Proteins / genetics*
  • Gene Rearrangement
  • Homeodomain Proteins / genetics*
  • Immunoglobulins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / genetics*
  • Recombination, Genetic*
  • Tumor Suppressor Proteins / genetics*
  • VDJ Recombinases / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Immunoglobulins
  • Tumor Suppressor Proteins
  • RAG-1 protein
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • VDJ Recombinases