TRIPLET REPEAT INSTABILITY IN YEAST AND HUMAN CELLS

酵母和人类细胞中的三重重复不稳定性

• 批准号: 6195208
• 负责人: Robert S Lahue
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195208
• 关键词: cytogenetics; fungal genetics; gene mutation; genetic regulatory element; genetic techniques; nucleic acid sequence; tissue /cell culture; transcription factor; yeasts

DESCRIPTION (Adapted from investigator's abstract): Eukaryotic genomes are replete with DNA microsatellites in which 1-5 base pairs are tandemly repeated. Microsatellites provide a useful "window" into the molecular mechanisms of genetic stability because these simple elements are hotspots for mutations that change the repeat length. For most simple repeats, tract alterations are typically limited to changes of 1-2 repeat units at a time. These sequences are stabilized by DNA mismatch repair, which corrects pre-mutagenic mispairs. In mismatch repair-deficient cells, the mutation frequency is greatly elevated at many microsatellites throughout the genome. Trinucleotide repeats (TNRs) exhibit very different genetic behavior. TNR expansions tend to be much longer and more frequents, once a critical threshold length has been achieved. These large expansions are not subject to mismatch repair because the large hairpin intermediates cannot be corrected. TNR alterations are highly localized; multiple TNRs have not been observed to undergo simultaneous, large alterations. These and other facts suggest that TNRs are subject to unique mutational mechanisms. The biomedical relevance of TNR instability stems from the fact that at least 14 human inherited diseases are caused by TNR expansions. TNR length in the androgen receptor gene is also a key risk factor in prostate cancer. This proposal focuses on the mechanisms of TNR instability in yeast and human cells. Genetic assays have been developed that allow specific identification of cells harboring altered TNR tracts. These assays allow analysis of the important DNA elements, such as thresholds, that govern TNR alterations. A genetic approach also allows isolation of the genes that control TNR instability.

描述(改编自研究人员摘要)：真核基因组 充满DNA微卫星，其中1-5个碱基对重复。 微卫星提供了一个有用的“窗口”，让我们了解 遗传稳定性，因为这些简单的元素是突变的热点 更改重复长度。对于大多数简单的重复，束改变是 通常一次仅限于改变1-2个重复单位。这些序列是 由DNA错配修复稳定，它纠正预致突变的错对。在……里面 错配修复缺陷细胞，突变频率在 基因组中有许多微卫星。 三核苷酸重复序列(TNR)表现出非常不同的遗传行为。TNR 扩张往往更长、更频繁，曾经是一个关键的门槛 长度已经达到。这些大型扩展不会受到错配的影响 因为大发夹中间件不能矫正，所以要修理。TNR 改变是高度局部性的；尚未观察到多个TNR 同时经历巨大的改变。这些和其他事实表明 TnRs受制于独特的突变机制。在生物医学上的相关性 TNR不稳定的原因是至少有14种人类遗传性疾病 是由TNR的扩张引起的。雄激素受体基因中的TNR长度也是 前列腺癌的关键风险因素。 这项建议侧重于TNR在酵母和人类中不稳定的机制 细胞。已经开发出基因分析方法，允许特定地识别 含有改变的TNR束的细胞。这些化验方法可以分析 控制TNR改变的重要DNA元素，如阈值。一个 基因方法也可以分离控制TNR的基因 不稳定。