Spinocerebellar ataxia 7 protein function.

描述（由申请人提供）：在真核细胞核中，DMA被组蛋白包装到核小体中，核小体是染色质的重复亚基。染色质对基因表达的调控涉及染色质修饰活性的作用，包括组蛋白乙酰转移酶（HATs）。HAT酶通常与含有其他转录调节因子的大型多蛋白共激活物复合物相关。这些观察结果为组蛋白乙酰化和转录调控的耦合提供了直接的分子基础。已知HAT蛋白与细胞癌蛋白和肿瘤抑制蛋白相关，并在与白血病相关的某些易位中被描述，因此被假定在癌症病因学以及病毒感染和核激素受体作用中发挥核心作用。SAGA （Spt- Ada-Gcn5乙酰转移酶）和SLIK （SAGA- like）是两个同源且高度保守的多亚基HAT复合物，最初在酵母中发现。我们已经鉴定出Sgf73/ySca7蛋白，它是人类蛋白ataxin-7的同源物，是SAGA和SLIK的一个组成部分。在其病理形态中，该蛋白与神经退行性疾病脊髓小脑性共济失调7 （SCA7）有关。酵母的Sca7对于SAGA和SLIK的完整性和功能都是必需的，而人类的多谷氨酰胺扩展版本的Sca7组装了一个特别缺乏核小体乙酰化的SAGA复合体。这些观察结果对人类Sca7蛋白在疾病发病机制中的功能具有重要意义。本研究的目标是利用酵母、哺乳动物细胞系和小鼠作为模型来阐明SCA7疾病病理背后的机制。具体目的是确定Sca7蛋白的功能，研究聚谷氨酰胺扩增对SAGA家族复合物在组蛋白修饰和转录调控中的功能的生化影响，并在小鼠模型中验证GCN5在CMS和视网膜中的功能缺失导致Sca7病理的假设。通过识别这些蛋白质的生理作用，可能有可能深入了解编码多聚谷氨酰胺束蛋白质的病理等位基因如何促进疾病进展。此外，我们的目标是研究使用组蛋白去乙酰化酶抑制剂治疗由SCA7扩增引起的细胞功能障碍。反过来，这可能为这种疾病和其他三核苷酸重复疾病（如亨廷顿氏病）提供可能的治疗方法。

DESCRIPTION (provided by applicant): In the eukaryotic cell nucleus, DMA is packaged by histones into nucleosomes, the repeating subunits of chromatin. The regulation of gene expression from chromatin involves the action of chromatin modifying activities including histone acetlytransferases (HATs). HAT enzymes are frequently associated with large multiprotein coactivator complexes that contain other transcriptional regulators. These observations have provided a direct molecular basis for the coupling of histone acetylation and the regulation of transcription. HAT proteins are known to associate with cellular oncoproteins and tumor suppressor proteins and have been described in certain translocations associated with leukemias and thus have been postulated to play a central role in the etiology cancer as well as viral infection and nuclear hormone receptor action. SAGA (Spt- Ada-Gcn5 Acetyltransferase) and SLIK (SAGA-Like) are 2 homologous and highly conserved multi-subunit HAT complexes that were originally identified in Saccharomyces cerevisiae. We have identified the protein Sgf73/ySca7, a homologue of the human protein ataxin-7, as a component of SAGA and SLIK. In its pathological form, this protein is responsible for the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Yeast Sca7 is necessary for the integrity and function of both SAGA and SLIK and a polyglutamine expanded version of human Sca7 assembles a SAGA complex that is specifically deficient in nucleosome acetylation. These observations have significant implications for the function of the human Sca7 protein in disease pathogenesis. The goals of this proposal are to use yeast, mammalian cell lines and mice as models to elucidate the mechanism behind the pathology of the SCA7 disorder. The Specific Aims are to determine the function of Sca7 protein, to examine the biochemical consequences of polyglutamine expansion on function of the SAGA family of complexes in histone modification and transcriptional regulation and test the hypothesis that depletion of GCN5 function in the CMS and retina contributes to SCA7 pathology in a mouse model. By identifying the physiological roles of these proteins it may be possible to gain insight as to how pathological alleles coding for proteins with polyglutamine tracts promote disease progression. Furthermore we aim to investigate the use of histone deacetylase inhibitors for the treatement of cellular dysfunction as a consequence SCA7 expansion. This, in turn, may suggest possible therapeutic treatments for this and other trinucleotide repeat diseases, such as Huntington's disease.