MICROSATELLITE INSTABILITY & DNA MISMATCH REPAIR SYSTEM

微卫星不稳定性

• 批准号: 7277826
• 负责人: John M Carethers
• 金额: $ 29.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7277826
• 关键词: ACVR2 gene; BAX gene; Bacteria; Base Pair Mismatch; Bax protein; Cancer Patient; Code; Colorectal Cancer; DNA; DNA Repair; DNA Structure; DNA-Directed DNA Polymerase; Data; Defect; Frameshift Mutation; Frequencies; Functional RNA; Gene Mutation; Gene Targeting; Genes; Genetic; Germ-Line Mutation; Growth; Human; Individual; Left; Malignant Neoplasms; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair; Mutate; Mutation; Nucleotides; PTEN gene; Pathogenesis; Pattern Recognition; Polymerase; Process; Rate; Repetitive Sequence; Syndrome; System; TGFBR2 gene; Testing; Tumor Suppressor Genes; Yeasts; base; design; insertion/deletion mutation; repaired

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.

描述（由申请人提供）：错配修复（MMR）是一种进化保守系统，它针对聚合酶错误修复新合成的DNA链。根据对细菌和酵母的研究，DNA MMR的组成部分似乎有特定的识别模式，尽管缺乏关于人类修复的数据。除了扭曲DNA链的单碱基对错配外，DNA MMR还可以检测到在称为微卫星的重复序列上形成的“环”，这可能是由DNA聚合酶的滑移引起的，在DNA链上留下了至少一个额外的核苷酸。结果是在微卫星上发生移码突变，这可以通过电泳检测到。大多数微卫星位于DNA的非编码区，但某些肿瘤抑制基因含有编码微卫星，当DNA MMR受损时，编码微卫星会发生移码突变。PTEN、TGFBR2、ACVR2和BAX的突变常见于Lynch综合征（由DNA MMR基因的种系突变引起）患者的癌症，或散发性微卫星不稳定结直肠癌。在本提案中，我们的总体假设是人类DNA错配修复系统具有特定的识别保真度，以修复帧移环为目标。基于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速率进行修复。同样，在目标基因中发现的有助于确定微卫星不稳定癌症生长增强的编码微卫星将根据错配修复缺陷的类型以不同的速率发生突变。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容易程度或能力。本文提出的研究旨在帮助理解靶基因在微卫星不稳定癌症中发生突变的原因和方式。这些研究对于了解微卫星不稳定结直肠癌的发病机制具有重要意义，并可能为中断突变过程的机制提供线索。