The Molecular Logic of Immunoglobulin Heavy Chain Class Switch Recombination

Class switch recombination (CSR) enables B cells to diversify antibody effector functions while preserving antigen specificity. This process involves activation-induced cytidine deaminase (AID)-mediated DNA lesions within transcribed donor and acceptor switch (S) regions of the Igh locus, followed by double-strand break repair through end-joining pathways. Recent advances have revealed that CSR is tightly regulated by transcriptional activation, chromatin topology, and dynamic loop extrusion, which together orchestrate the synapsis of distant S regions. Moreover, emerging evidence highlights the roles of transcriptional R-loops, G-quadruplex structures, and enhancer-driven chromatin remodeling in recruiting AID to S regions. In this article, we synthesize our current understanding of the mechanisms that control CSR, emphasizing how genome architecture and transcriptional dynamics collaborate with DNA repair pathways to maintain a balance between antibody diversity and genomic stability.