title: Higher-order looping and nuclear organization of Tcra facilitate targeted rag cleavage and regulated rearrangement in recombination centers.
abstract: V(D)J recombination is essential for generating a diverse array of B and T cell receptors that can recognize and combat foreign antigens. As with any recombination event, tight control is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One important aspect of regulation is directed targeting of the RAG recombinase. Indeed, RAG accumulates at the 3' end of individual antigen receptor loci poised for rearrangement; however, it is not known whether focal binding is involved in regulating cleavage, and what mechanisms lead to enrichment of RAG in this region. Here, we show that monoallelic looping out of the 3' end of the T cell receptor α (Tcra) locus, coupled with transcription and increased chromatin/nuclear accessibility, is linked to focal RAG binding and ATM-mediated regulation of monoallelic cleavage on looped-out 3' regions. Our data identify higher-order loop formation as a key determinant of directed RAG targeting and the maintenance of genome stability.
authors: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors: Julie
authors: J
authors: Chaumeil
authors: Mariann
authors: M
authors: Micsinai
authors: Panagiotis
authors: P
authors: Ntziachristos
authors: Ludovic
authors: L
authors: Deriano
authors: Joy M-H
authors: JM
authors: Wang
authors: Yanhong
authors: Y
authors: Ji
authors: Elphege P
authors: EP
authors: Nora
authors: Matthew J
authors: MJ
authors: Rodesch
authors: Jeffrey A
authors: JA
authors: Jeddeloh
authors: Iannis
authors: I
authors: Aifantis
authors: Yuval
authors: Y
authors: Kluger
authors: David G
authors: DG
authors: Schatz
authors: Jane A
authors: JA
authors: Skok
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056426:Genetic Loci; D042822:Genomic Instability; D006657:Histones / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; 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