Higher-order looping and nuclear organization of Tcra facilitate targeted rag cleavage and regulated rearrangement in recombination centers.

Julie Chaumeil (1) , Mariann Micsinai (1) , Panagiotis Ntziachristos (1) , Ludovic Deriano (2, 1) , Joy M-H Wang (1) , Yanhong Ji , Elphege P Nora (3) , Matthew J Rodesch (4) , Jeffrey A Jeddeloh (4) , Iannis Aifantis (1) , Yuval Kluger (5) , David G Schatz (6, 7) , Jane A Skok (1)

1 NYU - New York University School of Medicine
2 Développement lymphocytaire et Oncogénèse
3 Génétique et Biologie du Développement
4 Roche NimbleGen Inc.
5 Yale Cancer Center
6 Yale University [New Haven]
7 HHMI - Howard Hughes Medical Institute

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.

Keywords: *V(D)J Recombination; Alleles; Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins/metabolism; Cell Nucleus/metabolism; DNA-Binding Proteins/genetics/*metabolism; DNA Damage; Genetic Loci; Genomic Instability; Histones/genetics; Homeodomain Proteins/genetics/*metabolism; Mice; Inbred C57BL; Inbred CBA; Knockout; Protein-Serine-Threonine Kinases/metabolism; Receptors; Antigen; T-Cell; alpha-beta/genetics/*metabolism; Tumor Suppressor Proteins/metabolism

Domains: Life Sciences [q-bio]; Immunology

Julie Chaumeil, Mariann Micsinai, Panagiotis Ntziachristos, Ludovic Deriano, Joy M-H Wang, et al.. Higher-order looping and nuclear organization of Tcra facilitate targeted rag cleavage and regulated rearrangement in recombination centers.. Cell Reports, 2013, 3 (2), pp.359-70. ⟨10.1016/j.celrep.2013.01.024⟩. ⟨pasteur-01471693⟩