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Nucleic Acids Research Advance Access published online on August 30, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn542
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Non-conservative homologous recombination in human B lymphocytes is promoted by activation-induced cytidine deaminase and transcription

Maren Mierau1, Guido A. Drexler2,3, André Kutzera1, Kerstin Braunschmidt1, Joachim Ellwart4, Friederike Eckardt-Schupp2, Eberhard Fritz5, Jürgen Bachl6 and Berit Jungnickel1,*

1Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, National Research Center for Environmental Health, D-81377 Munich, 2Institute of Radiobiology, Helmholtz Center Munich, National Research Center for Environmental Health, D-85764 Neuherberg, 3Radiobiological Institute, Ludwig-Maximilians-University, D-80336 Munich, 4Institute of Molecular Immunology, Helmholtz Center Munich, National Research Center for Environmental Health, D-81377 Munich, 5Leibniz Institute for Age Research, Fritz Lipmann Institute, D-07745 Jena and 64-Antibody, WRO-1096.3, Schwarzwaldallee 215, CH-4002 Basel, Switzerland

*To whom correspondence should be addressed. Tel: +49 89 7099 209; Fax: +49 89 7099 500. Email: jungnickel{at}helmholtz-muenchen.de

Received July 8, 2008. Revised August 6, 2008. Accepted August 7, 2008.

During secondary immunoglobulin (Ig) diversification in vertebrates, the sequence of the variable region of Ig genes may be altered by templated or non-templated mechanisms. In both cases, cytidine deamination by activation-induced cytidine deaminase (AID) in the transcribed Ig loci leads to DNA lesions, which are repaired by conservative homologous recombination (HR) during Ig gene conversion, or by non-templated mutagenesis during somatic hypermutation. The molecular basis for the differential use of these two pathways in different species is unclear. While experimental ablation of HR in avian cells performing Ig gene conversion may promote a switch to somatic hypermutation, the activity of HR processes in intrinsically hypermutating mammalian cells has not been measured to date. Employing a functional HR assay in human germinal centre like B cell lines, we detect elevated HR activity that can be enhanced by transcription and AID. Products of such recombination events mostly arise through non-conservative HR pathways, while the activity of conservative HR is low to absent. Our results identify non-conservative HR as a novel DNA transaction pathway promoted by AID and suggest that somatic hypermutation in germinal centre B cells may be based on a physiological suppression of conservative HR.


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