Histone acetylation couples DNA replication to nucleosome assembly

组蛋白乙酰化将 DNA 复制与核小体组装结合起来

• 批准号: 7617252
• 负责人: Zhiguo Zhang
• 金额: $ 29.46万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617252
• 关键词: Acetyl Coenzyme A; Acetylation; Address; Affect; Aging; Animal Model; Binding; Biochemical; Biological Assay; Cell Cycle; Cell Survival; Cell physiology; Cells; Chromatin; Chromatin Modeling; Chromatin Remodeling Factor; Chromatin Structure; Chromosomal Breaks; Chromosomal Rearrangement; Complex; Coupled; Couples; Coupling; DNA; DNA Damage; DNA biosynthesis; Eukaryotic Cell; Event; Exhibits; Genetic; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; Histone Acetylation; Histone H3; Histones; Human; Inherited; Knowledge; Light; Lysine; Maintenance; Malignant Neoplasms; Mediating; Modification; Molecular; Molecular Chaperones; Nature; Normal Cell; Nuclear; Nucleosomes; Phase; Physiological; Play; Prevention; Process; Regulation; Replication-Associated Process; Role; Saccharomyces cerevisiae; Testing; Two-Dimensional Gel Electrophoresis; Yeasts; cancer cell; carcinogenesis; chromatin assembly factor I; chromatin immunoprecipitation; histone acetyltransferase; histone modification; in vivo; insight; mutant; novel

DESCRIPTION (provided by applicant): Maintenance of genome stability is essential for cell survival and is critical for the prevention of carcinogenesis. Indeed, genetic instability is one of the key features of cancer cells. Because errors in DNA replication are a major cause of genomic instability, it is critical to understand all aspects involved in the regulation of DNA replication. However, relatively few studies have addressed how chromatin structure, the physiological organization of DNA in eukaryotic cells, impacts and regulates the DNA replication process. During DNA replication, chromatin must be temporarily disassembled to allow the DNA replication machinery access to the DNA template. The newly-synthesized DNA strands are then immediately reassembled into their original chromatin state. Uncoupling of DNA synthesis and chromatin assembly results in genome instability. Because of the critical nature of genome stability, it is important to understand how DNA synthesis is coupled to chromatin assembly. We use the yeast Saccharomyces cerevisiae as a eukaryotic model organism to address questions regarding this essential, but poorly understood process. Recent studies have implicated the acetylation of lysine 56 on histone H3 (H3-K56) as a key regulatory event during the DNA synthesis and chromatin assembly. Acetylation of H3-K56 occurs transiently during S phase. Cells with altered acetylation of H3-K56 are highly sensitive to DNA damaging agents, suggesting that this modification is important for maintaining genome stability. The main objective of this proposal is to test the hypothesis that acetylation of H3-K56 by a novel and unique HAT Rtt109, which we have recently identified, maintains genome integrity by coupling DNA replication with the assembly of newly-replicated DNA into nucleosomes mediated by histone chaperones. Results from these studies will provide mechanistic insights into the role of histone modifications in coupling DNA synthesis with nucleosome assembly, an important aspect in the maintenance of genome stability and thus normal cell functions.

描述（由申请人提供）：维持基因组稳定性对于细胞生存至关重要，并且对于预防癌变至关重要。事实上，遗传不稳定性是癌细胞的关键特征之一。由于 DNA 复制错误是基因组不稳定的主要原因，因此了解 DNA 复制调控涉及的所有方面至关重要。然而，相对较少的研究涉及染色质结构（真核细胞中 DNA 的生理组织）如何影响和调节 DNA 复制过程。在 DNA 复制过程中，染色质必须暂时分解，以便 DNA 复制机器能够接触到 DNA 模板。新合成的 DNA 链随后立即重新组装成原始染色质状态。 DNA 合成和染色质组装的解偶联导致基因组不稳定。由于基因组稳定性的关键性质，了解 DNA 合成如何与染色质组装耦合非常重要。我们使用酿酒酵母作为真核模型生物来解决有关这一重要但知之甚少的过程的问题。最近的研究表明组蛋白 H3 (H3-K56) 上赖氨酸 56 的乙酰化是 DNA 合成和染色质组装过程中的关键调控事件。 H3-K56 的乙酰化在 S 期短暂发生。 H3-K56 乙酰化发生改变的细胞对 DNA 损伤剂高度敏感，表明这种修饰对于维持基因组稳定性很重要。该提案的主要目的是测试这样的假设：我们最近发现的一种新颖且独特的 HAT Rtt109 对 H3-K56 进行乙酰化，通过将 DNA 复制与新复制的 DNA 组装成由组蛋白伴侣介导的核小体耦合来维持基因组完整性。这些研究的结果将为了解组蛋白修饰在 DNA 合成与核小体组装耦合中的作用提供机制见解，这是维持基因组稳定性和正常细胞功能的一个重要方面。