Journal Article

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

Maren Mierau, Guido A. Drexler, André Kutzera, Kerstin Braunschmidt, Joachim Ellwart, Friederike Eckardt-Schupp, Eberhard Fritz, Jürgen Bachl and Berit Jungnickel

in Nucleic Acids Research

Volume 36, issue 17, pages 5591-5601
Published in print October 2008 | ISSN: 0305-1048
Published online August 2008 | e-ISSN: 1362-4962 | DOI: https://dx.doi.org/10.1093/nar/gkn542

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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.

Journal Article.  6251 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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