Regulation of the Germinal Center Reaction and Somatic Hypermutation Dynamics by Homologous Recombination.

Abstract:

During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell-specific inactivation of the critical HR factor Brca2, we detected decreased proliferation, survival, and thereby class switching of ex vivo-activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in Brca2-deficient mice. These mutation pattern changes in Brca2-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.

Citation: J Immunol. 2019 Sep 15;203(6):1493-1501. doi: 10.4049/jimmunol.1900483. Epub 2019 Aug 9.

Date Published: 15th Sep 2019

Authors: G. Hirth, Carl-Magnus Svensson, K. Bottcher, S. Ullrich, Marc Thilo Figge, Berit Jungnickel

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Created: 11th Feb 2021 at 15:07

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