Regulation of the germinal center reaction and somatic hypermutation dynamics by homologous recombination.
(2019) Regulation of the germinal center reaction and somatic hypermutation dynamics by homologous recombination. The Journal of Immunology [Epub ahead of print]
During somatic hypermutation of immunoglobulin (Ig) genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase (AID) are processed by multiple error-prone repair pathways. While error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at AID 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 detect 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 somatic hypermutation revealed that a certain fraction of DNA lesions at C:G base pairs 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 over time in Ctrl but not 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 somatic hypermutation and especially A:T mutagenesis.
doi: 10.4049/jimmunol.1900483 PMID: 31399517