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 hypermutation 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 polymerase-mediated 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.

p53 在基因组维护中起主要作用。除了在 DNA 修复控制中的多种 p53 功能外，体外还暗示了通过跨损伤合成对 DNA 损伤旁路的调节。用于抗体反应亲和力成熟的免疫球蛋白基因的体细胞超突变基于异常的转移聚合酶作用，必须受到严格控制以防止遗传改变和淋巴瘤发生。在研究 p53在体内体细胞超突变中的作用时，我们发现在所有器官中缺乏 p53 的小鼠中，跨病变聚合酶介导的 A:T 突变发生改变，但在 B 细胞特异性 p53 失活的小鼠中尤其如此，这意味着 p53 在非 B 细胞中的功能可能会改变 B 细胞中的突变。在类转换重组期间，当 p53 阻止染色体易位的形成时，我们还检测到 p53 在改变 G:C 和 A:T 诱变中的 B 细胞内在作用。因此，p53 调节跨损伤聚合酶活性，并在体内体细胞超突变与类转换重组期间显示出不同的活性。最后，p53 抑制导致人 B 淋巴瘤细胞中的体细胞超突变增加。我们得出结论，p53 功能的丧失可能通过以下方式促进遗传不稳定性体内抗体多样化过程中的多种途径。