Rad52 mediates class-switch DNA recombination to IgD

Yijiang Xu, Hang Zhou, Ginell Post, Hong Zan and Paolo Casali ()
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Yijiang Xu: University of Texas Long School of Medicine, UT Health Science Center
Hang Zhou: University of Texas Long School of Medicine, UT Health Science Center
Ginell Post: University of Arkansas School of Medicine
Hong Zan: University of Texas Long School of Medicine, UT Health Science Center
Paolo Casali: University of Texas Long School of Medicine, UT Health Science Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract In B cells, IgD is expressed together with IgM through alternative splicing of primary VHDJH-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, VHDJH-Cδs 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.

Date: 2022
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DOI: 10.1038/s41467-022-28576-2

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