Ruiz J F, Domínguez O, Laín de Lera T, Garcia-Díaz M, Bernad A, Blanco L
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma, Madrid, Spain.
Philos Trans R Soc Lond B Biol Sci. 2001 Jan 29;356(1405):99-109. doi: 10.1098/rstb.2000.0754.
A novel DNA polymerase (Pol mu) has been recently identified in human cells. The amino-acid sequence of Pol mu is 42% identical to that of terminal deoxynucleotidyl transferase (TdT), a DNA-independent DNA polymerase that contributes to antigen-receptor diversity. In this paper we review the evidence supporting the role of Pol mu in somatic hypermutation of immunoglobulin genes, a T-dependent process that selectively occurs at germinal centres: (i) preferential expression in secondary lymphoid organs; (ii) expression associated to developing germinal centres; and (iii) very low base discrimination during DNA-dependent DNA polymerization by Pol mu, a mutator phenotype enormously accentuated by the presence of activating Mn2+ ions. Moreover, its similarity to TdT, together with extrapolation to the crystal structure of DNA polymerase beta complexed (Pol beta) with DNA, allows us to discuss the structural basis for the unprecedented error proneness of Pol mu, and to predict that Pol mu is structurally well suited to participate also in DNA end-filling steps occurring both during V(D)J recombination and repair of DNA double-strand breaks that are processed by non-homologous end-joining.
最近在人类细胞中发现了一种新型DNA聚合酶（Pol mu）。Pol mu的氨基酸序列与末端脱氧核苷酸转移酶（TdT）有42%的同源性，TdT是一种不依赖DNA的DNA聚合酶，对抗原受体多样性有贡献。在本文中，我们综述了支持Pol mu在免疫球蛋白基因体细胞超突变中作用的证据，体细胞超突变是一种依赖T细胞的过程，选择性地发生在生发中心：（i）在二级淋巴器官中优先表达；（ii）与生发中心发育相关的表达；（iii）Pol mu在依赖DNA的DNA聚合过程中碱基识别能力极低，激活的Mn2+离子的存在极大地加剧了这种诱变表型。此外，它与TdT的相似性，以及对与DNA复合的DNA聚合酶β（Pol beta）晶体结构的推断，使我们能够讨论Pol mu前所未有的易错性的结构基础，并预测Pol mu在结构上也非常适合参与V（D）J重组和非同源末端连接处理的DNA双链断裂修复过程中发生的DNA末端填充步骤。
