| First Author | Xu Y | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 980 |
| PubMed ID | 35190531 | Mgi Jnum | J:338642 |
| Mgi Id | MGI:7255952 | Doi | 10.1038/s41467-022-28576-2 |
| Citation | Xu Y, et al. (2022) Rad52 mediates class-switch DNA recombination to IgD. Nat Commun 13(1):980 |
| abstractText | In B cells, IgD is expressed together with IgM through alternative splicing of primary VHDJH-Cmu-s-m-Cdelta-s-m RNAs, and also through IgD class switch DNA recombination (CSR) via double-strand DNA breaks (DSB) and synapse of Smu with sigmadelta. How such DSBs are resolved is still unknown, despite our previous report showing that Rad52 effects the 'short-range' microhomology-mediated synapsis of intra-Smu region DSBs. Here we find that induction of IgD CSR downregulates Zfp318, and promotes Rad52 phosphorylation and recruitment to Smu and sigmadelta, thereby leading to alternative end-joining (A-EJ)-mediated Smu-sigmadelta recombination with extensive microhomologies, VHDJH-Cdeltas transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52(-/-) 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 patients with systemic lupus erythematosus and in lupus-prone mice. Our findings thus show that Rad52 mediates IgD CSR through microhomology-mediated A-EJ in concert with Zfp318 downregulation. |
