Rad52 mediates class-switch DNA recombination to IgD

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• B cells express IgD alongside IgM via alternative splicing or DNA recombination.
• IgD class switch DNA recombination (CSR) involves double-strand DNA breaks (DSB) and synapsis of Sμ with σδ.
• The resolution mechanism of these DSBs remained largely unknown.

Purpose of the Study:

• To elucidate the mechanism of DSB resolution during IgD CSR.
• To investigate the role of Rad52 in IgD CSR.
• To explore the association of Rad52 activity with IgD-related autoimmune conditions.

Main Methods:

• Investigated IgD CSR in wild-type and Rad52-deficient mouse B cells.
• Utilized Rad52 knockdown in human B cells.
• Analyzed Rad52 phosphorylation and recruitment to Sμ and σδ regions.
• Examined IgD antibody responses and autoantibodies in patients with systemic lupus erythematosus and lupus-prone mice.

Main Results:

• IgD CSR induction downregulates Zfp318 and promotes Rad52 phosphorylation and recruitment.
• Rad52 mediates alternative end-joining (A-EJ) for Sμ-σδ recombination with extensive microhomologies.
• Rad52 ablation in mice and knockdown in humans abrogates IgD CSR.
• Rad52 phosphorylation correlates with high IgD CSR and anti-nuclear IgD autoantibodies in lupus patients and mice.

Conclusions:

• Rad52 is essential for IgD CSR through microhomology-mediated A-EJ, in conjunction with Zfp318 downregulation.
• Rad52 plays a critical role in IgD secretion and specific antibody responses.
• Dysregulated Rad52 activity in IgD CSR may contribute to autoimmune diseases like lupus.