title: UNG protects B cells from AID-induced telomere loss.
abstract: Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG). In contrast, in the absence of UNG activity, deleterious processing by mismatch repair leads to telomere loss and defective cell proliferation. Indeed, we show that UNG deficiency reduces B cell clonal expansion in the germinal center in mice and blocks the proliferation of tumor B cells expressing AID. We propose that AID-induced damage at telomeres acts as a fail-safe mechanism to limit the tumor promoting activity of AID when it overwhelms uracil excision repair.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cortizas
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Astrid
authors.initials: A
authors.lastname: Zahn
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.|Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 0G4, Canada.
authors.forename: Shiva
authors.initials: S
authors.lastname: Safavi
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136.
authors.forename: Joseph A
authors.identifier: 0000-0003-3252-0521
authors.initials: JA
authors.lastname: Reed
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Hematopathology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33146.
authors.forename: Francisco
authors.identifier: 0000-0001-5956-452X
authors.initials: F
authors.lastname: Vega
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada rverdun@med.miami.edu Javier.Di.Noia@ircm.qc.ca.|Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 0G4, Canada.|Department of Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Javier M
authors.initials: JM
authors.lastname: Di Noia
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136 rverdun@med.miami.edu Javier.Di.Noia@ircm.qc.ca.|Geriatric Research, Education, and Clinical Center, Miami VA Healthcare System, FL 33125.
authors.forename: Ramiro E
authors.identifier: 0000-0003-0530-4807
authors.initials: RE
authors.lastname: Verdun
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D049109:Cell Proliferation; D002999:Clone Cells; D003564:Cytidine Deaminase / Q000378:metabolism*; D019610:Cytoprotection; D004249:DNA Damage / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011485:Protein Binding; D011995:Recombination, Genetic / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000172:deficiency / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase