Parp3 negatively regulates immunoglobulin class switch recombination

PLoS Genet. 2015 May 22;11(5):e1005240. doi: 10.1371/journal.pgen.1005240. eCollection 2015 May.

Abstract

To generate highly specific and adapted immune responses, B cells diversify their antibody repertoire through mechanisms involving the generation of programmed DNA damage. Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by the recruitment of activation-induced cytidine deaminase (AID) to immunoglobulin loci and by the subsequent generation of DNA lesions, which are differentially processed to mutations during SHM or to double-stranded DNA break intermediates during CSR. The latter activate the DNA damage response and mobilize multiple DNA repair factors, including Parp1 and Parp2, to promote DNA repair and long-range recombination. We examined the contribution of Parp3 in CSR and SHM. We find that deficiency in Parp3 results in enhanced CSR, while SHM remains unaffected. Mechanistically, this is due to increased occupancy of AID at the donor (Sμ) switch region. We also find evidence of increased levels of DNA damage at switch region junctions and a bias towards alternative end joining in the absence of Parp3. We propose that Parp3 plays a CSR-specific role by controlling AID levels at switch regions during CSR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Base Sequence
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Gene Expression Regulation*
  • Genetic Loci
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Immunoglobulin Switch Region / genetics
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Recombination, Genetic
  • Somatic Hypermutation, Immunoglobulin / genetics

Substances

  • Immunoglobulin G
  • Immunoglobulin M
  • Poly(ADP-ribose) Polymerases
  • Parp2 protein, mouse
  • Cytidine Deaminase

Grant support

This work was supported by the Agence Nationale pour la Recherche [grant ANR-10-BLAN-1230 to BRSM and FD] http://www.agence-nationale-recherche.fr/; the Fondation ARC pour la Recherche sur le Cancer [Programme ARC to BRSM] http://www.fondation-arc.org/; the Institut National de la Santé et de la Recherche Médicale [Avenir-INSERM to BRSM] http://www.inserm.fr/; the Ministère de l'Enseignement Supérieur et de la Recherche [grant to LG] http://www.enseignementsup-recherche.gouv.fr/; La Ligue Nationale Contre le Cancer [Equipe labellisée to FD] http://www.ligue-cancer.net/; LabEx Medalis [to FD] http://medalis.unistra.fr/; and ANR-10-LABX-0030-INRT, a French State funded managed by the Agence Nationale de la Recherche under the program Investissements d'Avenir labelled ANR-10-IDEX-0002-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.