The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining

• Published in: Nature communications 2018-03, Vol.9 (1), p.1006-12, Article 1006
• Main Authors: Li, Conglei, Irrazabal, Thergiory, So, Clare C., Berru, Maribel, Du, Likun, Lam, Evelyn, Ling, Alexanda K., Gommerman, Jennifer L., Pan-Hammarström, Qiang, Martin, Alberto
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 631/250/1619/40/1774; 631/250/2152/2498; 64/60; 82/1; Animals; B-Lymphocytes; Class switching; Defects; Deoxyribonucleic acid; Deubiquitinating Enzymes - genetics; Deubiquitinating Enzymes - metabolism; DNA; DNA damage; DNA End-Joining Repair; DNA repair; Endopeptidases - genetics; Endopeptidases - metabolism; Eukaryotes; Female; Histones - genetics; Histones - metabolism; Homologous recombination; Homology; Humanities and Social Sciences; Immune response; Immune response (humoral); Immune system; Immunity, Humoral - genetics; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes - genetics; Isotypes; Lymphocytes B; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Non-homologous end joining; Primary Cell Culture; Repair; Science; Science (multidisciplinary); Ubiquitin; Ubiquitin - metabolism; V(D)J Recombination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03455-x

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. Class switch recombination (CSR) requires break and repair of immunoglobulin DNA. Here the authors show that the histone deubiquitinase Usp22 is involved in V(D)J recombination and CSR of IgG and IgE, but not IgA, and that IgG CSR is dependent on the canonical c-NHEJ pathway, whereas IgA CSR is more dependent on the alternative A-EJ pathway.