| First Author | Hirth G | Year | 2019 |
| Journal | J Immunol | Volume | 203 |
| Issue | 6 | Pages | 1493-1501 |
| PubMed ID | 31399517 | Mgi Jnum | J:279035 |
| Mgi Id | MGI:6360342 | Doi | 10.4049/jimmunol.1900483 |
| Citation | Hirth G, et al. (2019) Regulation of the Germinal Center Reaction and Somatic Hypermutation Dynamics by Homologous Recombination. J Immunol 203(6):1493-1501 |
| abstractText | 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. |
