Immunoglobulin class-switch DNA recombination: induction, targeting and beyond

Abstract

Class switch DNA recombination (CSR) of the immunoglobulin heavy chain (IgH) locus is central to the maturation of the antibody response and critically requires the AID cytidine deaminase. CSR entails changes of the chromatin state and transcriptional activation of the IgH locus upstream and downstream switch (S) regions that are to undergo S-S DNA recombination, induction of AID, and targeting of CSR factors to S regions by 14-3-3 adaptors and as enabled by the transcription machinery and histone modifications. In this Review, we focus on recent advances in CSR induction and targeting. We also outline an integrated model of the assembly of macromolecular complexes that transduce critical epigenetic information to enzymatic effectors of the CSR machinery.

Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination

“…However, the reduced levels of GLT for γ1 in FLKO mice argue against this, as this is the initial step in CSR to IgG1 that precedes AID-induced DNA damage (5).…”

“…In addition to B-cell receptor signals, primary and secondary stimuli control CSR in B cells. Whereas T-cell-dependent (i.e., CD40L) or T-cell-independent (i.e., TLR) primary stimuli induce expression of AID, secondary stimuli such as IL-4 (IgG1, IgE), IFN-γ (IgG2c), and TGF-β (IgA) are needed for directing the class switch to a specific antibody isotype through the induction of GLT (5).…”

Structural mechanism of ATP‐dependent DNA binding and DNA end bridging by eukaryotic Rad50

“…They arise during replication fork collapse or exposure to ionizing radiation, reactive oxygen species (ROS), or genotoxic chemicals (Sutherland et al, 2000;Costanzo et al, 2001;Pommier et al, 2003;Mahaney et al, 2009). DSBs are also enzymatically generated intermediates in meiotic recombination, V(D)J, and class switch recombination as well as yeast mating-type switching (Gapud & Sleckman, 2011;Haber, 2012;Xu et al, 2012;Lam & Keeney, 2015). Double-strand breaks can be repaired by different pathways.…”

Structure of the catalytic domain of Mre11 fromChaetomium thermophilum

“…On the other hand, DSBs are enzymatically introduced in a programmed fashion during meiosis and V(D)J or class-switch recombination during immunoglobulin development (Lam & Keeney, 2014;Gapud & Sleckman, 2011;Xu et al, 2012). To prevent chromosomal rearrangements and genome instability, organisms in all kingdoms of life have developed different DSB-repair pathways (Hanahan & Weinberg, 2011;Myung, Chen et al, 2001;Myung, Datta et al, 2001).…”