Parp3 Negatively Regulates Immunoglobulin Class Switch Recombination

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During infections, B cells diversify the antibodies they produce by two mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM mutates the regions encoding the antigen-binding site, generating high-affinity antibodies. CSR allows B cells to switch the class of antibody they produce (from IgM to IgA, IgG or IgE), providing novel effector functions. Together, SHM and CSR establish highly specific and pathogen-adapted antibody responses. SHM and CSR are initiated by the recruitment of the activation-induced cytidine deaminase (AID) enzyme to antibody genes. Once recruited, AID induces DNA lesions that are processed into mutations during SHM or chromosomal DNA breaks during CSR. These breaks activate multiple DNA repair proteins and are resolved by replacing the IgM gene segments by those encoding IgA, IgG or IgE. AID carries a significant oncogenic potential that needs to be controlled to preserve genome integrity. Nevertheless, the underlying mechanisms remain poorly understood. Here we show that Poly(ADP)ribose polymerase 3 (Parp3), an enzyme recently implicated in DNA repair, contributes to antibody diversification by negatively regulating CSR without affecting SHM. We show that Parp3 facilitates the repair of AID-induced DNA damage and controls AID levels on chromatin. We propose that Parp3 protects antibody genes from sustained AID-dependent DNA damage.

Vyšlo v časopise: Parp3 Negatively Regulates Immunoglobulin Class Switch Recombination. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005240
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005240

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