Senataxin promotes recombination fidelity during antigen receptor gene diversification

Functional redundancies exist between NHEJ and the ATM kinase-dependent chromatin DSB response, likely masking the activity of additional factors. Here, we performed targeted CRISPR/Cas9 knockout screens (+/- ATM kinase inhibition) in pro-B cells and identified Senataxin (SETX) as a novel player in V(D)J recombination.

We show that SETX supports V(D)J recombination, particularly when the ATM kinase is inhibited or in an XLF-deficient background. Furthermore, we show that SETX suppresses the formation of aberrant coding end-to-signal end hybrid joints during V(D)J recombination, both in vitro and in vivo. Finally, SETX prevents the aberrant joining of AID-induced DNA ends during class switch recombination (CSR).