title: It takes two: communication between homologous alleles preserves genomic stability during V(D)J recombination.
abstract: Chromosome pairing is involved in X chromosome inactivation, a classic instance of monoallelic gene expression. Antigen receptor genes are also monoallelically expressed ("allelically excluded") by B and T lymphocytes, and we asked whether pairing contributed to the regulation of V(D)J recombination at these loci. We found that homologous immunoglobulin (Ig) alleles pair up during recombination. Homologous Ig pairing is substantially reduced in the absence of the RAG1/RAG2 recombinase, but a transgene expressing an active site RAG1 mutant (which binds but does not cleave DNA) rescues pairing in Rag1(-/-) developing B cells. RAG-mediated cleavage on one allele induces the other allele to relocate to pericentromeric heterochromatin (PCH), likely to ensure that only one allele is cut at a time. This relocation to PCH requires the DNA damage sensor ATM (ataxia telengiectasia mutated). In the absence of ATM, repositioning at PCH is diminished and the incidence of cleavage on both alleles is significantly increased. ATM appears to be activated by the introduction of a double-strand break on one allele to act in trans on the uncleaved allele, repositioning or maintaining it at PCH, to prevent bi-allelic recombination and chromosomal translocations.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Vicky L
authors.initials: VL
authors.lastname: Brandt
authors.forename: Susannah L
authors.initials: SL
authors.lastname: Hewitt
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002875:Chromosomes / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D025521:Tumor Suppressor Proteins; C064655:V(D)J recombination activating protein 2; C475961:gamma-H2AX protein, mouse; C064658:RAG-1 protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases