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

• Published in: Nature immunology Vol. 10; no. 6; pp. 655 - 664
• Main Authors: Marszalek, Katarzyna, Salvagiotto, Giorgia, Sleckman, Barry P, Schatz, David G, Farrar, Michael A, Ghysdael, Jacques, Skok, Jane A, Busslinger, Meinrad, Yin, Bu, Bassing, Craig H, Tenthorey, Jeannette, Ramsey, Laura B, Hewitt, Susannah L, Chaumeil, Julie, Steinel, Natalie, Ji, Yanhong
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2009
• Subjects: Alleles; Animals; Antibody diversity; Ataxia Telangiectasia Mutated Proteins; B-Lymphocytes - metabolism; Cell Cycle Proteins - genetics; Cells, Cultured; DNA Breaks; DNA-Binding Proteins - genetics; Gene Rearrangement; Genetic aspects; Genetic recombination; Homeodomain Proteins - genetics; Immunoglobulins - genetics; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Physiological aspects; Properties; Protein Serine-Threonine Kinases - genetics; Recombinases; Recombination, Genetic; Tumor Suppressor Proteins - genetics; VDJ Recombinases - metabolism; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1735

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.