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

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 breakag...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2019-09, Vol.203 (6), p.1493-1501
Main Authors: Hirth, Gianna, Svensson, Carl-Magnus, Böttcher, Katrin, Ullrich, Steffen, Figge, Marc Thilo, Jungnickel, Berit
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - physiology
BRCA2 Protein - genetics
Cytidine Deaminase - genetics
DNA - genetics
DNA Damage - genetics
Female
Genes, Immunoglobulin - genetics
Germinal Center - physiology
Homologous Recombination - genetics
Lymphocyte Activation - genetics
Male
Mice
Mice, Inbred C57BL
Mutation - genetics
Somatic Hypermutation, Immunoglobulin - genetics
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Summary: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 , 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 -deficient mice. These mutation pattern changes in -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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1900483