Marra G, Schär P
Institute for Medical Radiobiology, Zürich, Switzerland.
Biochem J. 1999 Feb 15;338 ( Pt 1)(Pt 1):1-13.
Misincorporation of non-complementary bases by DNA polymerases is a major source of the occurrence of promutagenic base-pairing errors during DNA replication or repair. Base-base mismatches or loops of extra bases can arise which, if left unrepaired, will generate point or frameshift mutations respectively. To counteract this mutagenic potential, organisms have developed a number of elaborate surveillance and repair strategies which co-operate to maintain the integrity of their genomes. An important replication-associated correction function is provided by the post-replicative mismatch repair system. This system is highly conserved among species and appears to be the major pathway for strand-specific elimination of base-base mispairs and short insertion/deletion loops (IDLs), not only during DNA replication, but also in intermediates of homologous recombination. The efficiency of repair of different base-pairing errors in the DNA varies, and appears to depend on multiple factors, such as the physical structure of the mismatch and sequence context effects. These structural aspects of mismatch repair are poorly understood. In contrast, remarkable progress in understanding the biochemical role of error-recognition proteins has been made in the recent past. In eukaryotes, two heterodimers consisting of MutS-homologous proteins have been shown to share the function of mismatch recognition in vivo and in vitro. A first MutS homologue, MSH2, is present in both heterodimers, and the specificity for mismatch recognition is dictated by its association with either of two other MutS homologues: MSH6 for recognition of base-base mismatches and small IDLs, or MSH3 for recognition of IDLs only. Mismatch repair deficiency in cells can arise through mutation, transcriptional silencing or as a result of imbalanced expression of these genes.
DNA聚合酶误掺入非互补碱基是DNA复制或修复过程中发生促诱变碱基配对错误的主要来源。碱基错配或额外碱基环可能出现，如果不修复，将分别产生点突变或移码突变。为了抵消这种诱变潜力，生物体已经开发了许多精细的监测和修复策略，这些策略协同作用以维持其基因组的完整性。复制后错配修复系统提供了一种重要的与复制相关的校正功能。该系统在物种间高度保守，似乎是链特异性消除碱基错配和短插入/缺失环（IDL）的主要途径，不仅在DNA复制过程中，而且在同源重组中间体中也是如此。DNA中不同碱基配对错误的修复效率各不相同，似乎取决于多种因素，如错配的物理结构和序列上下文效应。错配修复的这些结构方面了解甚少。相比之下，最近在理解错误识别蛋白的生化作用方面取得了显著进展。在真核生物中，由MutS同源蛋白组成的两个异二聚体已被证明在体内和体外共享错配识别功能。第一个MutS同源物MSH2存在于两个异二聚体中，错配识别的特异性由其与另外两个MutS同源物之一的结合决定：MSH6用于识别碱基错配和小IDL，或MSH3仅用于识别IDL。细胞中的错配修复缺陷可能通过突变、转录沉默或这些基因的表达失衡而产生。
