title: Apurinic/apyrimidinic endonuclease 2 regulates the expansion of germinal centers by protecting against activation-induced cytidine deaminase-independent DNA damage in B cells.
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.
authors.affiliation: Department of Molecular and Physiological Systems, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655; Department of Pathology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands; and.
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.affiliation: Department of Molecular and Physiological Systems, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Erin K
authors.initials: EK
authors.lastname: Linehan
authors.affiliation: Department of Molecular and Physiological Systems, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Nada
authors.initials: N
authors.lastname: Esa
authors.affiliation: Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuchimoto
authors.affiliation: Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Department of Molecular and Physiological Systems, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Robert T
authors.initials: RT
authors.lastname: Woodland
authors.affiliation: Department of Molecular and Physiological Systems, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655; carol.schrader@umassmed.edu.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Schrader
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D064251:Multifunctional Enzymes; D018384:Oxidative Stress / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D064251:Multifunctional Enzymes; D051560:Proto-Oncogene Proteins c-bcl-6; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C476886:Apex2 protein, mouse; D004720:Endonucleases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase