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: 6636518
• 负责人: Robert S Lahue
• 金额: $ 24.16万
• 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/6636518
• 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（改编自研究者摘要）：真核基因组是 充满了DNA微卫星，其中1-5个碱基对串联重复。 微卫星提供了一个有用的“窗口”，进入分子机制， 遗传稳定性，因为这些简单的元件是突变的热点， 改变重复长度。对于大多数简单的重复序列， 通常限于一次改变1-2个重复单元。这些序列 通过DNA错配修复来稳定，这纠正了诱变前的错配。在 错配修复缺陷细胞，突变频率大大提高， 许多微卫星遍布整个基因组。 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，一旦一个关键的门槛， 长度已经实现。这些大的扩张不受不匹配的影响 因为大的发夹中间体不能被纠正。TNR 改变是高度局部化的;尚未观察到多个TNR， 同时发生大的变化这些和其他事实表明， TNR受到独特的突变机制的影响。的生物医学意义 TNR不稳定源于至少14种人类遗传性疾病 是由TNR扩张引起的。雄激素受体基因中的TNR长度也是 前列腺癌的一个关键风险因素。 本研究主要探讨酵母和人类TNR不稳定性的机制， 细胞已经开发了允许特异性鉴定 TNR束改变的细胞。这些测定允许分析 重要的DNA元件，如阈值，控制TNR改变。一 遗传学方法也允许分离控制TNR的基因 不稳定