Apurinic/apyrimidinic endonuclease 2 regulates the expansion of germinal centers by protecting against activation-induced cytidine deaminase-independent DNA damage in B cells

Jeroen E.J. Guikema, Erin K. Linehan, Nada Esa, Daisuke Tsuchimoto, Yusaku Nakabeppu, Robert T. Woodland, Carol E. Schrader

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Activation-induced cytidine deaminase (AID) initiates a process generating DNA mutations and breaks in germinal center (GC) B cells that are necessary for somatic hypermutation and class-switch recombination. GC B cells can "tolerate" DNA damage while rapidly proliferating because of partial suppression of the DNA damage response by BCL6. In this study, we develop a model to study the response of mouse GC B cells to endogenous DNA damage. We show that the base excision repair protein apurinic/apyrimidinic endonuclease (APE) 2 protects activated B cells from oxidative damage in vitro. APE2-deficient mice have smaller GCs and reduced Ab responses compared with wild-type mice. DNA double-strand breaks are increased in the rapidly dividing GC centroblasts of APE2-deficient mice, which activate a p53-independent cell cycle checkpoint and a p53-dependent apoptotic response. Proliferative and/or oxidative damage and AID-dependent damage are additive stresses that correlate inversely with GC size in wild-type, AID-, and APE2-deficient mice. Excessive double-strand breaks lead to decreased expression of BCL6, which would enable DNA repair pathways but limit GC cell numbers. These results describe a nonredundant role for APE2 in the protection of GC cells from AID-independent damage, and although GC cells uniquely tolerate DNA damage, we find that the DNA damage response can still regulate GC size through pathways that involve p53 and BCL6.

Original languageEnglish
Pages (from-to)931-939
Number of pages9
JournalJournal of Immunology
Volume193
Issue number2
DOIs
Publication statusPublished - Jul 15 2014

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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