Hypermutation of Immunoglobulin Genes in Memory B Cells of DNA Repair-deficient Mice

doi:10.1084/jem.187.11.1735

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J. Exp. Med., Volume 187, Number 11, June 1, 1998 1735-1743

Hypermutation of Immunoglobulin Genes in Memory B Cells of DNA Repair-deficient Mice

By Heinz Jacobs,^* Yosho Fukita, Gijsbertus T.J. van der Horst,^§ Jan de Boer,^§ Geert Weeda,^§ Jeroen Essers,^§ Niels de Wind, Bevin P. Engelward, Leona Samson, Sjef Verbeek,^¶ Josiane Ménissier de Murcia,^** Gilbert de Murcia,^** Hein t e Riele, and Klaus Rajewsky

From the ^* Basel Institute for Immunology, CH-4005 Basel, Switzerland; the Institute for Genetics, University of Cologne, 50931 Cologne, Germany; the ^§ Department of Cellular Biology and Genetics, Erasmus University, 3000 DR Rotterdam, The Netherlands; the Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; the ^¶ Department of Immunology, University Hospital Utrecht, 3508 GA Utrecht, The Netherlands; the ^** Ecole Superieure de Biotechnologie de Strasbourg, Université Louis Pasteur, F-67400 Illkirch-Graffenstaden, France; and the Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, Massachusetts 02115

To investigate the possible involvement of DNA repair in the process of somatic hypermutation of rearranged immunoglobulinvariable (V) region genes, we have analyzed the occurrence, frequency,distribution, and pattern of mutations in rearranged V $lambda$ 1 lightchain genes from naive and memory B cells in DNA repair-deficientmutant mouse strains. Hypermutation was found unaffected in micecarrying mutations in either of the following DNA repair genes:xeroderma pigmentosum complementation group (XP)A and XPD, Cockaynesyndrome complementation group B (CSB), mutS homologue 2 (MSH2),radiation sensitivity 54 (RAD54), poly (ADP-ribose) polymerase(PARP), and 3-alkyladenine DNA-glycosylase (AAG). These resultsindicate that both subpathways of nucleotide excision repair,global genome repair, and transcription-coupled repair are notrequired for somatic hypermutation. This appears also to be truefor mismatch repair, RAD54-dependent double-strand-break repair,and AAG-mediated base excision repair.

Key words: DNA repair; DNA repair-deficient mice; memory B cells; naive B cells; somatic mutations

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