Rad52 mediates class-switch DNA recombination to IgD.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35190531.
- Also identified by DOI 10.1038/s41467-022-28576-2 and PMC identifier 8861003.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
In B cells, IgD is expressed together with IgM through alternative splicing of primary V<sub>H</sub>DJ<sub>H</sub>-Cμ-s-m-Cδ-s-m RNAs, and also through IgD class switch DNA recombination (CSR) via double-strand DNA breaks (DSB) and synapse of Sμ with σδ. How such DSBs are resolved is still unknown, despite our previous report showing that Rad52 effects the 'short-range' microhomology-mediated synapsis of intra-Sμ region DSBs. Here we find that induction of IgD CSR downregulates Zfp318, and promotes Rad52 phosphorylation and recruitment to Sμ and σδ, thereby leading to alternative end-joining (A-EJ)-mediated Sμ-σδ recombination with extensive microhomologies, V<sub>H</sub>DJ<sub>H</sub>-Cδs transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52<sup>-/-</sup> 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.
Medical subject headings
- Immunoglobulin Class Switching
- Immunoglobulin D
- Rad52 DNA Repair and Recombination Protein