Rad52 mediates class-switch DNA recombination to IgD

In B cells, IgD is mainly expressed together with IgM alternative splicing of a long primary mRNA transcript containing the rearranged VDJ exons and the Cm and Cd exons, but also independently through IgD class switch DNA recombination (CSR) via double-strand DNA breaks (DSBs) and synapse of Sm with sd, but how such DSBs are resolved is still unknown. Rad52 has been implicated previously in a short-range microhomology-mediated synapsis of intra-Sm region DSBs. Here we find that induction of IgD CSR downregulates Zfp318 and promotes Rad52 phosphorylation and recruitment to Sm and sd, leading to alternative end-joining (A-EJ)-mediated Sm-sd recombination with extensive microhomologies, VHDJH-Cds transcription, and sustained IgD secretion. Rad52 ablation in mouse Rad52 knockout B cells aborts IgD CSR in vitro and in vivo, and dampens the specific IgD antibody response to OVA; Rad52 knockdown in human B cells also abrogates IgD CSR. Finally, Rad52 phosphorylation is associated with high levels of IgD CSR and anti-nuclear IgD autoantibodies in lupus-prone mice and patients with lupus. Our findings thus show that Rad52 mediates IgD CSR through microhomology-mediated A-EJ in concert with Zfp318.