HISTONE ACETYLTRANSFERASE AND TRANSCRIPTIONAL REGULATION

描述（申请人摘要的逐字记录）：组蛋白 乙酰转移酶是非常保守的蛋白质，其中许多发挥着关键作用 转录调控中的作用。组蛋白突变或失调 乙酰化可导致恶性肿瘤、发育缺陷和病毒 发病机制。然而，人们对转录是如何进行的了解甚少。 在超乙酰化染色质区域内增强。已经有好几个 为解释基因被激活的机制而提出的假设 组蛋白乙酰转移酶。为了更好地理解这些机制， 研究人员将使用芽殖酵母酿酒酵母 Gcn5p 蛋白 作为测试以下假设的模型：1）一个或多个早期步骤 Gcn5p 酶促作用促进转录激活。 2） Gcn5p 乙酰化组蛋白尾部结构域可能会招募特定蛋白质 染色质区域高度乙酰化，进而激活转录。 3） 非组蛋白可作为 Gcn5p 作用的底物。乙酰化 Gcn5p 的这些蛋白质在转录中发挥积极作用。 4）两个 酵母、SAGA 和 ADA 中的 Gcn5p-conta.in HAT 复合物可能表现不同 发挥调节 HIS3 表达的作用。具体来说，基因筛查 挽救由于缺乏 Gcn5p HAT 导致的转录缺陷的抑制剂 活性，针对特异性结合乙酰化组蛋白尾部的蛋白质，以及 建议使用非组蛋白 Gcn5p 底物。此外，个人角色 ADA 和 SAGA 复合物在 HIS3 表达中的作用有待研究 遗传和生化方面。

DESCRIPTION (Verbatim from the applicant's abstract): Histone acetyltransferases are well conserved proteins many of which play critical roles in regulating transcription. Mutations or misregulation of histone acetylation can lead to malignancies, developmental defects and viral pathogenesis. It is however poorly understood as to how transcription is enhanced within a hyperacetylated chromatin region. There have been several hypotheses put forth to explain the mechanisms by which genes are activated by histone acetyltransferases. To better understand these mechanisms, the investigator will use the budding yeast Saccharomyces cerevisiae Gcn5p protein as a model to test the following hypotheses: 1) One or more of the early steps of transcriptional activation is facffitated by the Gcn5p enzymatic action. 2) Gcn5p-acetylated histone tail domains may recruit specific proteins to the hyperacetylated chromatin region which in turn activates transcription. 3) Non-histone proteins may serve as substrates for Gcn5p action. Acetylation of these proteins by Gcn5p plays positive roles in transcription. 4) The two Gcn5p-conta.in HAT complexes in yeast, SAGA and ADA, may perform different functions in regulating HIS3 expression. Specifically, genetic screening for suppressors that rescue the transcription defects due to the lack of Gcn5p HAT activity, for proteins that bind specifically the acetylated histone tails, and for non-histone Gcn5p substrates are proposed. Moreover, individual roles played by the ADA and SAGA complexes in HIS3 expression are to be investigated both genetically and biochemically.