Mechanisms of Genetic Instabilites of Triplet Repeats

描述(申请人摘要)：遗传不稳定性(扩展和 简单重复序列的删除)在生命周期中是重要的 无论是原核细胞还是真核细胞。这一基本机制 在支原体、细菌、酵母、哺乳动物细胞和 在人类身上。在低等生物中，这些遗传多态是 控制基因表达的阶段变化。在人类中， 简单重复序列的扩展和删除与 癌症的病因以及遗传性神经疾病。 先前的工作表明，DNA复制和DNA复制介导了DNA的扩张 通过滑移重复序列的互补链以形成修复 具有不同相对稳定性的发夹环状结构。校长 研究人员最近证明，重组是一种强大的 用于生成大型扩展的机制。在某种程度上，这项工作可以 推断为人类疾病，重组可能是 脆性X综合征、强直性肌营养不良和SCA8中发现的大扩张。 第一个具体目标是阐明基因重组的机制。 它们介导了三联重复序列(TRS)的扩展。特定目标2将 评价双链断裂的重组修复在遗传学中的作用 不稳定因素。第三个具体目标是建立一种针对 确定重组频率。特定目标4将调查TANDER RecA细胞体内基于复制的不稳定性。 总而言之，首席研究员将研究分子 导致基因突变的机制(复制、重组、修复) 简单重复序列中的不稳定性。

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.