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Pol ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability

¹ Immune Disease Institute, Boston, MA 02115
² Harvard Medical School, Boston, MA 02115
³ Institute for Genetics, University of Cologne, D-50674 Cologne, Germany
⁴ The Children's Hospital, Boston, MA 02115
⁵ Howard Hughes Medical Institute, Chevy Chase, MD 20815

CORRESPONDENCE Klaus Rajewsky: rajewsky{at}idi.med.harvard.edu

Pol is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Pol, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Pol in SHM, Pol deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredundant role of Pol in DNA DSB repair through nonhomologous end joining.

D. Schenten's present address is Dept. of Immunobiology, Yale Medical School, New Haven, CT 06520.

G. Esposito's present address is TaconicArtemis, 51063 Cologne, Germany.

U. Klein's present address is Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.

Abbreviations used: AID, activation-induced deaminase; CSR, class switch recombination; DSB, double-strand break; ES, embryonic stem; FISH, fluorescence in situ hybridization; GC, germinal center; NHEJ, nonhomologous end joining; SHM, somatic hypermutation; SKY, spectral karyotyping; V, variable.

© 2009 Schenten et al.
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