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

Nucleic Acids Res. 36, 5591-5601 (2008)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords DOUBLE-STRAND BREAKS; CLASS SWITCH RECOMBINATION; PRONE DNA-REPAIR; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; DIRECTED REPAIR; ATM PROTEIN; EXPRESSION
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Quellenangaben Volume: 36, Issue: 17, Pages: 5591-5601 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed