Context-dependent regulation of immunoglobulin mutagenesis by p53

p53 plays a major role in genome maintenance. In addition to multiple p53 functions in the control of DNA repair, a regulation of DNA damage bypass via translesion synthesis has been implied in vitro. Somatic hyper mutation of immunoglobulin genes for affinity maturation of antibody responses is based on aberrant translesion polymerase action and must be subject to stringent control to prevent genetic alterations and lymphomagenesis. When studying the role of p53 in somatic hypermutation in vivo, we found altered translesion polymerasemediated A:T mutagenesis in mice lacking p53 in all organs, but notably not in mice with B cell-specific p53 inactivation, implying that p53 functions in non-B cells may alter mutagenesis in B cells. During class switch recombination, when p53 prevents formation of chromosomal translocations, we in addition detected a B cell intrinsic role for p53 in altering G:C and A:T mutagenesis. Thus, p53 regulates translesion polymerase activity and shows differential activity during somatic hypermutation versus class switch recombination in vivo. Finally, p53 inhibition leads to increased somatic hypermutation in human B lymphoma cells. We conclude that loss of p53 function may promote genetic instability via multiple routes during antibody diversification in vivo.

Automated summary

p53 plays a crucial role in maintaining genome stability by regulating DNA repair and translesion synthesis. Mice lacking p53 show altered translesion polymerase-mediated mutagenesis, suggesting a potential role of p53 in non-B cells affecting B cell mutations. Inhibition of p53 leads to increased somatic hypermutation in human B lymphoma cells, indicating that loss of p53 function may promote genetic instability in vivo during antibody diversification.