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© Deriano Lab / Institut Pasteur
Chromosomes métaphasiques d’une cellule lymphoïde cancéreuse présentant une amplification des gènes Igh et c-myc
Publication : Nature communications

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 01 Jan 2013

Chaumeil J, Micsinai M, Ntziachristos P, Roth DB, Aifantis I, Kluger Y, Deriano L, Skok JA

Link to Pubmed [PMID] – 23900513

Nat Commun 2013;4:2231

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.

http://www.ncbi.nlm.nih.gov/pubmed/23900513