The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage.

Julie Chaumeil (1) , Mariann Micsinai (1, 2) , Panagiotis Ntziachristos (1) , David B Roth (3) , Iannis Aifantis (1) , Yuval Kluger (2) , Ludovic Deriano (4) , Jane A Skok (1)

1 NYU - New York University School of Medicine
2 YSM - Yale School of Medicine [New Haven, Connecticut]
3 University of Pennsylvania
4 Développement lymphocytaire et Oncogénèse

Tight control of antigen-receptor gene rearrangement is required to preserve genome integrity and prevent the occurrence of leukaemia and lymphoma. Nonetheless, mistakes can happen, leading to the generation of aberrant rearrangements, such as Tcra/d-Igh inter-locus translocations that are a hallmark of ataxia telangiectasia-mutated (ATM) deficiency. Current evidence indicates that these translocations arise from the persistence of unrepaired breaks converging at different stages of thymocyte differentiation. Here we show that a defect in feedback control of RAG2 activity gives rise to bi-locus breaks and damage on Tcra/d and Igh in the same T cell at the same developmental stage, which provides a direct mechanism for generating these inter-locus rearrangements. Both the RAG2 C-terminus and ATM prevent bi-locus RAG-mediated cleavage through modulation of three-dimensional conformation (higher-order loops) and nuclear organization of the two loci. This limits the number of potential substrates for translocation and provides an important mechanism for protecting genome stability.

Keywords: *Gene Rearrangement; alpha-Chain T-Cell Antigen Receptor; *Gene Rearrangement; delta-Chain T-Cell Antigen Receptor; *Genomic Instability; Animals; Ataxia Telangiectasia Mutated Proteins/*metabolism; DNA-Binding Proteins/*chemistry/*metabolism; Genetic Loci; Mice; Receptors; Antigen; T-Cell; alpha-beta/genetics

Domains: Immunology

Julie Chaumeil, Mariann Micsinai, Panagiotis Ntziachristos, David B Roth, Iannis Aifantis, et al.. The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage.. Nature Communications, 2013, 4, pp.2231. ⟨10.1038/ncomms3231⟩. ⟨pasteur-01471697⟩