MICROSATELLITE INSTABILITY & DNA MISMATCH REPAIR SYSTEM

描述(申请人提供)：错配修复(MMR)是一种进化保守的系统，针对新合成的DNA链上的聚合酶错误进行修复。基于细菌和酵母的研究，DNA MMR的成分似乎有特定的识别模式，尽管缺乏关于人类修复的数据。除了导致DNA链扭曲的单碱基对错配外，DNA MMR还可以检测在被称为微卫星的重复序列上形成的“环”，推测是由DNA聚合酶的滑动引起的，DNA聚合酶在DNA链上留下至少一个额外的核苷酸。其结果是微卫星上的移码突变，可以用电泳法检测到。大多数微卫星位于DNA的非编码区，但某些肿瘤抑制基因包含编码微卫星，当DNA MMR受损时，这些微卫星会发生移码突变。PTEN、TGFBR2、ACVR2和Bax突变常见于Lynch综合征患者的癌症(由DNA MMR基因的胚系突变引起)，或散发性微卫星不稳定结直肠癌。在这个建议中，我们的总体假设是，人类DNA错配修复系统在靶向修复移码环方面具有特定的识别保真度。根据DNA错配修复系统的个体缺陷，我们提出非编码微卫星将以不同的修复速度进行修复。同样，在靶基因中发现的编码微卫星有助于确定微卫星不稳定癌症的增强生长，将根据错配修复缺陷的类型以不同的速度发生突变。我们假设，除了特定的错配修复缺陷外，周围的DNA结构可能会影响编码微卫星突变的易感性或能力。这里提出的研究旨在帮助理解为什么以及如何在微卫星不稳定癌症中发生靶基因突变。这些研究对了解微卫星不稳定性结直肠癌的发病机制具有重要意义，并可能为阻断突变过程的机制提供线索。

DESCRIPTION (provided by applicant): Mismatch Repair (MMR) is an evolutionary conserved system that targets polymerase mistakes for repair on the newly synthesized DNA strand. Based on bacteria and yeast studies, there appears to be specific recognition patterns by components of DNA MMR, although data on human repair is lacking. In addition to single base pair mismatches that distort the DNA strand, DNA MMR can detect "loops" formed at repetitive sequences termed microsatellites, presumably caused by slippage by the DNA polymerase that leaves at least one extra nucleotide on a DNA strand. The result is a frameshift mutation at the microsatellite, which can be detected electrophoretically. Most microsatellites are in non-coding regions of DNA, but certain tumor suppressor genes contain coding microsatellites that develop frameshift mutations when DNA MMR is impaired. Mutations of PTEN, TGFBR2, ACVR2, and BAX are often found in cancers from patients with Lynch syndrome (caused by germline mutation of a DNA MMR gene), or in sporadic microsatellite unstable colorectal cancers. In this proposal, our overall hypothesis is that the human DNA mismatch repair system has specific recognition fidelity in targeting repair of frameshifted loops. We propose based on the individual defect of the DNA mismatch repair system that non-coding microsatellites will be repaired at varied rates. Similarly, coding microsatellites found in target genes that help determine the enhanced growth of microsatellite unstable cancers will become mutated at varying rates based on the type of mismatch repair defect. We hypothesize that in addition to a specific mismatch repair defect, the surrounding DNA structure may influence the ease or ability of a coding microsatellite to become mutated. The studies proposed here are designed to help understand why and how target genes become mutated in microsatellite unstable cancer. These studies are important to understanding the pathogenesis of microsatellite unstable colorectal cancer, and may provide clues to a mechanism for interrupting the mutation process.