Why are microsatellites unstable?

本研究旨在了解人类群体中微卫星多样性的分子机制，以及这些微卫星在病理条件下，特别是在肿瘤细胞中的不稳定性，从而阐明微卫星的真正动力学及其在高等真核生物中的致病意义。首先，我们观察到人类群体中单核苷酸微卫星多态性的极度缺乏，这与二核苷酸微卫星动态形成了鲜明的对比。接下来，我们分析了在各种遗传背景下的单核苷酸和二核苷酸微卫星改变，因此，发现这两类微卫星的动态是不同的，这取决于DNA错配修复（MMR）和DNA聚合酶校对（PPR）的缺陷。使用缺乏MMR和PPR的小鼠胚胎成纤维细胞的分析正在进行中。

This study aimed to understand the molecular mechanisms that underlie the diversity of microsatellites in human populations and the instability of those in the pathological conditions, particularly, in tumour cells, and, consequently, to elucidate the bona fide dynamics of microsatellites and its pathogenic significance in higher eukaryotic organisms. First, we observed the extreme paucity of polymorphisms in mononucleotide microsatellites among human populations, which makes a remarkable contrast to the dinucleotide microsatellite dynamics. We next analysed mononucleotide and dinucleotide microsatellite alterations under various genetic backgrounds and, consequently, found that the dynamics of these two categories of microsatellites are distinctive depending on the defects in DNA mismatch repair (MMR) and DNA polymerase proofreading (PPR). Analyses using mouse embryo fibroblasts lacking both MMR and PPR are now underway.