MICROSATELLITE INSTABILITY & DNA MISMATCH REPAIR SYSTEM

微卫星不稳定性

• 批准号: 7674694
• 负责人: John M Carethers
• 金额: $ 1.22万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674694
• 关键词: ACVR2 gene; BAX gene; Bacteria; Base Pair Mismatch; 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; Repetitive Sequence; Syndrome; System; TGFBR2 gene; Testing; Tumor Suppressor Genes; Yeasts; base; design; human DNA; 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，其靶向聚合酶错误以修复新合成的DNA链。基于细菌和酵母菌的研究，似乎有特定的识别模式的组成部分的DNA MMR，虽然数据对人类的修复是缺乏。除了扭曲DNA链的单碱基对错配之外，DNA MMR还可以检测在称为微卫星的重复序列上形成的“环”，这可能是由DNA聚合酶在DNA链上留下至少一个额外核苷酸的滑动引起的。其结果是微卫星上的移码突变，可以通过遗传学检测到。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，这些微卫星会发生移码突变。PTEN、TGFBR 2、ACVR 2和BAX的突变经常在Lynch综合征患者的癌症（由DNA MMR基因的种系突变引起）或散发性微卫星不稳定的结直肠癌中发现。在这个提议中，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中具有特定的识别保真度。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被修复。类似地，在靶基因中发现的有助于确定微卫星不稳定癌症的增强生长的编码微卫星将基于错配修复缺陷的类型以不同的速率突变。我们假设，除了特定的错配修复缺陷之外，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突变的原因和方式。这些研究对于理解微卫星不稳定性结直肠癌的发病机制非常重要，并可能为中断突变过程的机制提供线索。