Mechanisms of Genetic Instabilites of Triplet Repeats

描述（申请人摘要）：遗传不稳定性（扩增和 简单重复序列的缺失）在 包括原核和真核细胞。这一基本机制 已在支原体、细菌、酵母、哺乳动物细胞中发现诱变， 在人类身上。在低等生物中，这些遗传多态性是 控制基因表达的相位变化。人类的 简单重复序列的扩增和缺失与 癌症以及遗传性神经系统疾病的病因。 先前的工作已经揭示，扩增是由DNA复制介导的， 通过重复序列的互补链的滑动进行修复， 具有不同相对稳定性的发夹环结构。校长 研究人员最近证明，重组是一种强有力 产生大规模扩张的机制。在某种程度上，这项工作可以 外推到人类疾病，重组可能是一个重要的机制， 在脆性X综合征、强直性肌营养不良和SCA 8中发现的大扩增。 第一个具体目标是阐明遗传重组的机制 其介导三联体重复序列（TRS）扩增。具体目标2将 评估双链断裂的重组修复在遗传学中的作用 不稳定性第三个具体目标是建立一种基因测定法， 确定重组频率。Specific Aim 4将研究串联 recA-细胞中基于复制的体内不稳定性。 总之，主要研究者将研究分子 导致遗传的机制（复制、重组、修复） 简单重复序列的不稳定性。

DESCRIPTION (Applicant's abstract): Genetic instabilities (expansion and deletions of simple repeating sequences) are important in the life cycles of both prokaryotic and eukaryotic cells. This fundamental mechanism of mutagenesis has been found in mycoplasma, bacteria, yeast, mammalian cells, and in humans. In lower organisms, these genetic polymorphisms are the basis for phase variations which control the expression of genes. In humans, the expansions and deletions of simple repeating sequences are closely tied to the etiologies of cancers as well as hereditary neurological diseases. Prior work has revealed that expansions are mediated by DNA replication and repair by the slippage of the complementary strands of the repeats to form hairpin loop structures with differing relative stabilities. The principal investigator has recently demonstrated that recombination is a powerful mechanism for generating large expansions. To the extent that this work can be extrapolated to human diseases, recombination may be an important mechanism for the large expansions found in fragile X syndrome, myotonic dystrophy, and SCA8. The first Specific Aim is to elucidate the mechanisms of genetic recombination which mediate the triplet repeat sequence (TRS) expansions. Specific Aim 2 will evaluate the role of recombinational repair of double strand breaks in genetic instabilities. The third Specific Aim is to establish a genetic assay for determining the recombination frequency. Specific Aim 4 will investigate tandem duplication-based instabilities in vivo in recA- cells. In summary, the principal investigator will investigate the molecular mechanisms (replication, recombination, repair) that cause genetic instabilities in simple repeat sequences.