HISTONE ACETYLTRANSFERASE AND TRANSCRIPTIONAL REGULATION

描述(逐字摘自申请者摘要)：组蛋白 乙酰转移酶是保守的蛋白质，其中许多起着关键作用。 在转录调控中的作用。组蛋白的突变或调控不当 乙酰化可导致恶性肿瘤、发育缺陷和病毒 发病机制。然而，对于转录是如何进行的，人们却知之甚少 在高乙酰化的染色质区域内增强。已经有几个 提出假说来解释基因被激活的机制 组蛋白乙酰转移酶。为了更好地理解这些机制， 研究人员将使用萌芽酵母酿酒酵母Gcn5p蛋白 作为检验以下假设的模型：1)一个或多个早期步骤 转录激活的影响因素是Gcn5p的酶作用。2) Gcn5p-乙酰化组蛋白尾部结构域可能会将特定的蛋白质招募到 高乙酰化的染色质区域，进而激活转录。3) 非组蛋白可作为Gcn5p作用的底物。乙酰化 这些被Gcn5p激活的蛋白在转录过程中起着积极的作用。4)两个 酵母、SAGA和ADA中的HAT复合体中的Gcn5p-Conta.可能表现不同 在调节HIS3表达中的作用。具体地说，基因筛查 修复由于缺乏Gcn5p HAT而导致的转录缺陷的抑制子 活性，对于特定结合乙酰化组蛋白尾部的蛋白质，以及 对于非组蛋白，提出了Gcn5p底物。此外，个人角色 ADA和SAGA复合体在HIS3表达中的作用有待研究 在基因和生化上都是如此。

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.