INSTABILITY OF SIMPLE REPETITIVE DNA SEQUENCES IN YEAST

描述：微卫星是DNA中的一个单一碱基或一个 少量的碱基重复多次。所有真核生物都被检查过了 到目前为止，这些卫星中都有微卫星。这些序列本质上是不稳定的， 发生长度变化的速度比观察到的要快得多 用于“正常”的DNA序列。全基因组的微卫星不稳定性是 与某些类型的人类癌症有关。在酵母中，DNA的突变 错配修复基因导致微卫星不稳定和一些人类 具有不稳定微卫星的肿瘤在人类同源物中有突变 酵母DNA错配修复基因。一些不稳定的微卫星肿瘤， 然而，缺乏这样的突变。在目前的提案中，突变筛选 旨在识别影响酵母微卫星不稳定性的新基因 都被提出了。如果发现新的基因，这些基因的人类同源物 将会被隔离。从具有不稳定微卫星的肿瘤中提取DNA 在已知的DNA错配修复基因中没有突变的将是 检查以确定这些肿瘤在人类中是否存在突变 新发现的酵母基因的同源物。 与微卫星不稳定性有关的其他三种类型的实验是 建议。因为DNA复制过程中的错误很可能会 造成微卫星不稳定性，即在酵母中寻找突变 导致不稳定微卫星的DNA聚合酶增量将是 已执行。第二，微卫星在中国的遗传调控 将对酵母中的线粒体DNA进行研究。第三，转基因小鼠品系 将被建造成允许测量微卫星的不稳定性 在活体内。

DESCRIPTION: Microsatellites are regions of DNA in which a single base or a small number of bases is repeated multiple times. All eukaryotes examined thus far contain microsatellites. These sequences are inherently unstable, undergoing alterations in length at a much higher rate than that observed for "normal" DNA sequences. Genome-wide microsatellite instability is associated with certain types of human cancer. In yeast, mutations in DNA mismatch repair genes result in microsatellite instability and some human tumors with unstable microsatellites have mutations in human homologues of the yeast DNA mismatch repair genes. Some microsatellite unstable tumors, however, lack such mutations. In the current proposal, mutant screens designed to identify new genes affecting microsatellite instability in yeast are proposed. If new genes are identified, human homologues of these genes will be isolated. DNA isolated from tumors with unstable microsatellites that do not have mutations in known DNA mismatch repair genes will be examined to determine whether these tumors have mutations in human homologues of the newly-discovered yeast genes. Three other types of experiments concerning microsatellite instability are proposed. Since mistakes made during DNA replication are likely to contribute to microsatellite instability, a search for mutations in yeast DNA polymerase delta that result in unstable microsatellites will be performed. Second, the genetic regulation of microsatellite in mitochondrial DNA in yeast will be studied. Third, a transgenic mouse line will be constructed to allow the measurement of microsatellite instability in vivo.