Langerak Petra, Nygren Anders O H, Krijger Peter H L, van den Berk Paul C M, Jacobs Heinz
The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
J Exp Med. 2007 Aug 6;204(8):1989-98. doi: 10.1084/jem.20070902. Epub 2007 Jul 30.
B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine(164) of proliferating cell nuclear antigen (PCNA(K164)) stimulates TLS. To determine the role of PCNA(K164) modifications in somatic hypermutation, PCNA(K164R) knock-in mice were generated. PCNA(K164R/K164R) mutants are born at a sub-Mendelian frequency. Although PCNA(K164R/K164R) B cells proliferate and class switch normally, the mutation spectrum of hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction of mutations at template A/T is associated with a compensatory increase at G/C, which is a phenotype similar to polymerase eta (Poleta) and mismatch repair-deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Poleta likely cooperate in establishing mutations at template A/T during replication of Ig genes.
B细胞利用跨损伤DNA合成（TLS）在由活化诱导的胞苷脱氨酶引起的遗传损伤周围引入体细胞突变。增殖细胞核抗原赖氨酸（164）位点的单泛素化（PCNA（K164））刺激TLS。为了确定PCNA（K164）修饰在体细胞高频突变中的作用，构建了PCNA（K164R）基因敲入小鼠。PCNA（K164R/K164R）突变体以低于孟德尔遗传频率的数量出生。尽管PCNA（K164R/K164R）B细胞增殖和类别转换正常，但超突变免疫球蛋白（Ig）基因的突变谱发生了显著改变。模板A/T处突变的强烈减少与G/C处的补偿性增加相关，这是一种类似于聚合酶η（Polη）和错配修复缺陷B细胞的表型。错配识别、单泛素化PCNA和Polη可能在Ig基因复制过程中协同作用，在模板A/T处建立突变。
