title: RAG-1 and ATM coordinate monoallelic recombination   and nuclear positioning of immunoglobulin loci.
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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Susannah L
authors.initials: SL
authors.lastname: Hewitt
authors.forename: Bu
authors.initials: B
authors.lastname: Yin
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ji
authors.forename: Julie
authors.initials: J
authors.lastname: Chaumeil
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Marszalek
authors.forename: Jeannette
authors.initials: J
authors.lastname: Tenthorey
authors.forename: Giorgia
authors.initials: G
authors.lastname: Salvagiotto
authors.forename: Natalie
authors.initials: N
authors.lastname: Steinel
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D053960:DNA Breaks; D004268:DNA-Binding Proteins / Q000235:genetics*; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011995:Recombination, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D045567:VDJ Recombinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D025521:Tumor Suppressor Proteins; C064658:RAG-1 protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D045567:VDJ Recombinases