Abstract
Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in γH2AX and impairs the classical non-homologous end joining (c-NHEJ), affecting both V(D)J recombination and CSR. Surprisingly, Usp22 depletion causes defects in CSR to various Ig isotypes, but not IgA. We further demonstrate that IgG CSR primarily relies on c-NHEJ, whereas CSR to IgA is more reliant on the alternative end joining pathway, indicating that CSR to different isotypes involves distinct DNA repair pathways. Hence, Usp22 is the first deubiquitinase reported to regulate both V(D)J recombination and CSR in vivo by facilitating c-NHEJ.
Highlights
Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions
We further demonstrated that CSR to IgG/IgE is primarily mediated by cNHEJ, whereas CSR to IgA is more dependent on MH-mediated alternative end joining (A-EJ)
Consistent with a previous report that measured serum Ig isotypes in 53BP1−/− mice[36], we found by measuring surface Ig isotypes that 53BP1−/− B cells exhibited a less severe defect in IgA CSR than CSR to other Ig isotypes
Summary
Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. We further demonstrate that IgG CSR primarily relies on c-NHEJ, whereas CSR to IgA is more reliant on the alternative end joining pathway, indicating that CSR to different isotypes involves distinct DNA repair pathways. I.e., V(D)J recombination, creates the primary antibody repertoire and forms the antigen binding domain of the antibody[1] This process involves the generation and subsequent repair of RAG1/2-induced double-stranded DNA breaks (DSBs) at specific recombination signal sequences that flank each V, D, and J coding segment within the variable region[1]. IgG CSR is primarily mediated by the c-NHEJ pathway, whereas IgA CSR is more dependent on alternative end joining, indicating that CSR to different isotypes may involve distinct DNA repair pathways. By creating the first KO mice of the SAGA complex, we show that Usp[22] has an important function in repairing DSBs that occur during B-cell development
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