FUNCTIONAL ANALYSIS OF THE SIR2 SILENCING PROTEIN

成功的转录沉默每个人的大部分 真核基因组至关重要，因为不适当的基因表达 导致灾难性后果，包括致癌 转型。拟议研究的长期目标是 了解转录沉默的基本机制。 酵母菌沉默基因Sir2同源基因的发现 从原核生物到哺乳动物的各种生物都建立了 沉默研究的重要新焦点。最新进展 为人类类SIR沉默提供了第一个证据 提示Sir2沉默功能可以分开 从基因上来说。提出的研究的主要目标是 旨在解决有关Sir2的长期悬而未决的问题 本身以及在最初的 功能保守的沉默结构域的特征。这个 该项目的目标是：.推广生化和细胞生物学 Sir2沉默蛋白的分析。追求对Sir2的分析 蛋白质结构域被确定为其在沉默和 它的特殊性。识别S1R2相互作用的分子，以便 了解Sir2p的活性机制及其调控 功能。这些目标将通过基因， 生物化学和细胞生物学方法。所取得的成果将 导致对沉默的染色质复合体的更多了解 转录调控和基因组调控的机制 从酵母菌保存到人类。在理解这些方面取得了进展 至关重要的监管机制最终可能导致 改进的诊断和改进的治疗和遗传 对基因丢失引起的人类疾病的干预 监管。

Successful transcriptional silencing of the majority of each eukaryotic genome is critical because inappropriate gene expression leads to disastrous consequences, including oncogenic transformation. The long-term goal of the proposed research is to understand fundamental mechanisms of transcriptional silencing. Discovery of homologs of the yeast silencing gene SIR2 from organisms as diverse as prokaryotes and mammals established an important new focus for studying silencing. Recent progress provides the first evidence for SIR-like silencing in humans and suggests that SIR2 silencing functions may be separated genetically. The primary goals of the research proposed are designed to address long-standing unanswered questions about SIR2 itself and specific questions and hypotheses raised in initial characterization of functionally conserved silencing domains. The project aims are to: .Extend biochemical and cell biological analyses of the SIR2 silencing protein. Pursue analysis of Sir2 protein domains identified for their significance in silencing and its specificity. Identify S1R2 interacting molecules in order to understand the mechanism of Sir2p's activity and regulation of its function. These aims will be accomplished through genetic, biochemical and cell biological approaches. Results obtained will lead to greater knowledge of silenced chromatin complexes and mechanisms of transcriptional control and genomic regulation conserved from yeast to humans. Progress made understanding these centrally important regulatory mechanisms may ultimately lead to improved diagnostics and refined therapeutic and genetic interventions for human diseases resulting from loss of gene regulation.