Investigate the downstream mechanisms and upstream regulation of acetyltransferas

研究乙酰转移酶的下游机制和上游调控

• 批准号: 7628410
• 负责人: HUI ZOU
• 金额: $ 29.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628410
• 关键词: Acetylation; Acetyltransferase; Affect; Affinity; Antibodies; Basic Science; Binding; Biochemical; Biological Process; Bruck-de Lange syndrome; Cells; Centromere; Chromosomal Instability; Chromosome Arm; Chromosomes; Complex; Cytoplasm; DNA; DNA Repair; Drosophila genus; Drug Delivery Systems; Ensure; Eukaryota; Genetic Transcription; Haspin; Hela Cells; Hereditary Disease; Histone Acetylation; Histone Code; Histone H3; Histones; Homologous Gene; In Vitro; Interphase Cell; Lead; Malignant Neoplasms; Mediating; Medical; Methods; Mitosis; Mitotic; Molecular Weight; Mutation; Nature; Nucleosomes; Pathway interactions; Phosphorylation; Proteins; Regulation; Research; Roberts-SC phocomelia syndrome; Role; Saccharomycetales; Sister Chromatid; Small Interfering RNA; System; Testing; Threonine; Yeasts; cancer therapy; chromatin remodeling; cohesin; cohesion; histone acetyltransferase; in vivo; overexpression; small molecule

DESCRIPTION (provided by applicant): San is a putative acetyltransferase that is essential for viability and sister chromatid cohesion in Drosophila, but its homologue is completely dispensable in budding yeast. This raises the question whether the cohesion function of San is conserved. We found that, in HeLa cells, both San and its enzymatic activity are required for sister chromatid cohesion, specifically at the centromeres but not chromosome arms. This indicates that San is required for a cohesion mechanism that is conserved only in metazoans. The study of a metazoan- specific factor is critical for the understanding of sister chromatid cohesion in higher eukaryotes, which is poorly understood and notably different from that in yeast. In terms of medical applications, chromosome instability strongly associates with cancers. Moreover, cohesion molecules have been implicated in genetic disorders, such as Roberts Syndrome and Cornelia de Lange Syndrome. The following studies will contribute to basic science research and could lead to important medical applications. The short-term objective is to understand how San mediates sister chromatid cohesion. Although not modifying any of the known cohesion factors in vitro, San acetylates many chromosome-associated proteins. Identification of the substrates is critical for revealing the downstream mechanisms. Regarding the upstream regulation, San localizes to the cytoplasm in interphase cells and its activity is regulated by an inhibitory mechanism. This proposal will build on the above findings and focus on the role of San in sister chromatid cohesion, specifically the downstream substrates and upstream regulation. The long-term objective is to build a comprehensive understanding of the functions of San. San acetylates many substrates. It is highly possible that some substrates are involved in functions different from sister chromatid cohesion. The proposed study will provide entry points for additional functions of San. In addition, San may be used as a drug target for cancer therapy. Identification of small molecules that modulate the San mechanism may provide practical medical applications.

描述（由申请人提供）：San 是一种推定的乙酰转移酶，对于果蝇的活力和姐妹染色单体的凝聚力至关重要，但其同源物在芽殖酵母中完全是可有可无的。这就提出了 San 的内聚函数是否守恒的问题。我们发现，在 HeLa 细胞中，San 及其酶活性都是姐妹染色单体凝聚所必需的，特别是在着丝粒处，但在染色体臂处则不然。这表明 San 是仅在后生动物中保守的内聚机制所必需的。后生动物特异性因子的研究对于理解高等真核生物中姐妹染色单体的凝聚力至关重要，而高等真核生物中的姐妹染色单体凝聚力目前知之甚少，并且与酵母中的姐妹染色单体凝聚力显着不同。在医学应用方面，染色体不稳定性与癌症密切相关。此外，内聚分子与遗传性疾病有关，例如罗伯茨综合症和科妮莉亚·德·朗格综合症。以下研究将有助于基础科学研究，并可能带来重要的医学应用。短期目标是了解 San 如何介导姐妹染色单体的凝聚力。尽管在体外没有改变任何已知的凝聚因子，但 San 乙酰化了许多染色体相关蛋白。底物的识别对于揭示下游机制至关重要。关于上游调节，San定位于间期细胞的细胞质，其活性受到抑制机制的调节。该提案将建立在上述发现的基础上，重点关注 San 在姐妹染色单体凝聚力中的作用，特别是下游底物和上游调节。长期目标是全面了解 San 的功能。 San 乙酰化许多底物。某些底物很可能参与与姐妹染色单体内聚不同的功能。拟议的研究将为 San 的附加功能提供切入点。此外，San还可作为癌症治疗的药物靶点。鉴定调节 San 机制的小分子可能会提供实际的医学应用。