Differential regulation of immunoglobulin class switch recombination by the tumor suppressor p53

Abstract

Immunoglobulin class switch recombination (CSR) plays an important role in humoral immune response enabling B cells to replace the initial IgM by another antibody class (IgG, IgE or IgA), thus changing the effector functions of antibodies. CSR occurs between highly repetitive switch sequences located upstream of constant gene exons, and is initiated by the Activation-Induced cytidine Deaminase via transcription-dependent deamination of single-stranded DNA targets at switch regions. CSR is preceded by germline transcription and is controlled by the super-enhancer 3' regulatory region (3'RR) in an activation-specific manner. The 3'RR is composed of four enhancers (hs3a, hs1-2, hs3b, and hs4) which act in synergy, and its long-range activity correlates with the enhancers' transcription. In addition to its function as a tumor suppressor, the p53 transcription factor controls various developmental and cellular processes. This multifaceted function is largely due to its context-dependent transcriptional activity, involving both activation and repression of a myriad of target genes. Despite its potential importance for CSR, which implies multiple layers of transcriptional, epigenetic and DNA break/repair regulations, the role of p53 in CSR is still unclear. Here, by using a mouse line devoid of p53, we show that p53 regulates CSR in an isotype-specific manner. Moreover, we provide evidence that p53 has a dual role in the control of germline transcription as it acts both as an activator and a repressor. Finally, we show that p53 is required for hs4 transcription, suggesting a role for p53 in the regulation of the 3'RR's transcriptional activity.