RAG-1 and ATM coordinate monoallelic recombination   and nuclear positioning of immunoglobulin loci.
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.
Hewitt
Susannah L
SL
Department of Pathology, New York University School of Medicine, New York, New York, USA.
Yin
Bu
B
Ji
Yanhong
Y
Chaumeil
Julie
J
Marszalek
Katarzyna
K
Tenthorey
Jeannette
J
Salvagiotto
Giorgia
G
Steinel
Natalie
N
Ramsey
Laura B
LB
Ghysdael
Jacques
J
Farrar
Michael A
MA
Sleckman
Barry P
BP
Schatz
David G
DG
Busslinger
Meinrad
M
Bassing
Craig H
CH
Skok
Jane A
JA
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
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