Fiche publication
Date publication
octobre 2025
Journal
Science signaling
Auteurs
Membres identifiés du Cancéropôle Est :
Dr REINA-SAN-MARTIN Bernardo
Tous les auteurs :
Libri AB, Wang J, Marton T, Yu W, Dossin F, Balmus G, Reina-San-Martin B, Frock R, Lescale C, Deriano L
Lien Pubmed
Résumé
Antigen receptor diversity depends on the assembly of variable (V), diverse (D), and joining (J) exons in genes encoding immunoglobulins (Igs) and T cell receptors (TCRs). During V(D)J recombination, DNA double-strand breaks (DSBs) introduced by the RAG1/2 nuclease complex are repaired by the process of nonhomologous end-joining (NHEJ). We hypothesized that functional redundancies between NHEJ and the chromatin DSB response, which depends on the kinase ATM, potentially masked the activity of additional factors that regulate V(D)J recombination. We performed targeted CRISPR-Cas9 knockout screens for genes implicated in V(D)J recombination in pro-B cells that were either untreated or treated with an ATM inhibitor. We found that loss of the RNA/DNA helicase senataxin (SETX) impaired V(D)J recombination and led to the formation of aberrant hybrid joints between coding ends and signal ends, both in vitro and in mice. The loss of SETX in a background deficient in the NHEJ factor XLF or in which ATM was inhibited led to substantial impairment of V(D)J recombination and to the presence of unsealed coding ends. SETX limited aberrant activation-induced cytidine deaminase (AID)-induced DNA end-joining between -containing alleles during the process of class-switch recombination. Together, our findings reveal a previously uncharacterized role for SETX in promoting recombination fidelity during antigen receptor gene diversification.
Mots clés
Animals, V(D)J Recombination, genetics, Mice, DNA End-Joining Repair, RNA Helicases, genetics, Ataxia Telangiectasia Mutated Proteins, genetics, DNA Breaks, Double-Stranded, Multifunctional Enzymes, CRISPR-Cas Systems, Mice, Knockout, DNA Helicases, genetics, Humans, Receptors, Antigen, T-Cell, genetics, Precursor Cells, B-Lymphoid, metabolism
Référence
Sci Signal. 2025 10 14;18(908):eadv8801
