Temporal-spatial control of mitotic regulators by polySUMOylation

通过多SUMO化对有丝分裂调节因子进行时空控制

• 批准号: 10718546
• 负责人: Yanchang Wang
• 金额: $ 33.08万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718546
• 关键词: Affect; Anaphase; Biochemistry; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chromosome Segregation; Chromosomes; Complex; DNA Damage; DNA Repair; Data; Development; Disease; Ensure; Eukaryota; Event; Genome Stability; Genomic Instability; Goals; Human; Kinetochores; Knowledge; Lysine; Macromolecular Complexes; Malignant Neoplasms; Mitosis; Mitotic; Molecular; Nuclear; Nucleolar Proteins; Outcome; PLK1 gene; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Regulation; Research; Ribosomal DNA; Role; Saccharomycetales; Sumoylation Pathway; System; Testing; Translating; Ubiquitin; Ubiquitination; Work; Yeasts; biological adaptation to stress; cancer diagnosis; cancer therapy; chemical genetics; experimental study; novel therapeutic intervention; polypeptide; prevent; protein complex; protein function; repaired; response; scaffold; telophase; tool; treatment strategy; ubiquitin ligase; yeast genetics

Abstract SUMOylation is an essential post-translational modification that adds small ubiquitin-like modifiers (SUMO) to protein lysine residues. SUMOylation regulates many cellular functions, including cell proliferation, DNA repair, and stress response. Deregulation of SUMOylation contributes to genome instability and cancer development. Attachment of single SUMO to proteins often creates scaffolds to nucleate macromolecular interactions. On the other hand, attachment of chains of SUMO (polySUMOylation) often triggers protein ubiquitination and extraction from a macromolecular complex. Recent works demonstrate polySUMO-dependent relocation of damaged DNA, which facilitates damage repair. However, the function of protein polySUMOylation and its regulation during cell cycle remain poorly defined. Our long-term goal is to uncover the molecular mechanisms that control genome stability to provide fundamental knowledge that will help develop treatment strategies for diseases resulting from genome instability, such as cancer. The objective of this project is to investigate how polySUMOylation controls the relocation of two key mitotic regulators during the cell cycle: the RENT (regulator of nucleolar silencing and telophase) critical for mitotic exit, and the CPC (chromosomal passenger complex), essential for chromosome bipolar attachment. We recently found that polySUMOylation induction in yeast cells triggers relocation of these two critical mitotic regulators. Our preliminary data support the central hypothesis that polySUMOylation promotes relocation of some key mitotic regulators for successful anaphase initiation, and activation of polo-like kinase triggers polySUMOylation by phosphorylating a deSUMOylase. Our objective will be attained via the following specific aims: 1) Elucidate the mechanism of polySUMOylation-triggered nucleolar protein delocalization that promotes mitotic exit. 2) Determine how polySUMOylation of CPC subunits promotes CPC translocation. 3) Investigate the temporal control mechanism for polySUMOylation during the cell cycle. To test our hypothesis and achieve our aims, we will combine budding yeast genetics, cell biology, and biochemistry. Successful completion of this research will provide a comprehensive understanding of how polySUMOylation controls subcellular localization of protein complexes in the context of cell cycle. Given the exceptional conservation of both the SUMO system and the cell cycle machinery, principles proved in budding yeast are highly likely to translate to human and other eukaryotes. The results will have an important positive impact on the cell biology field because they will uncover new mechanisms critical for genome stability and unveil new targets for cancer diagnosis and therapy.

摘要 SUMO化是一种必要的翻译后修饰，它将小泛素样修饰物(SUMO)添加到 蛋白质赖氨酸残基。和甲基化调节许多细胞功能，包括细胞增殖、DNA修复、 和压力反应。SUMO化的解除调控会导致基因组不稳定和癌症的发展。 单个相扑附着在蛋白质上通常会产生支架，以形成大分子相互作用的核心。论 另一方面，相扑(多糖基化)链的连接通常会触发蛋白质的泛素化和提取 来自一种大分子复合体。最近的工作证明了依赖于PolySUMO的受损DNA的重新定位， 这有助于损伤修复。然而，蛋白质多糖基化的功能及其在细胞中的调节 周期仍然定义不清。我们的长期目标是发现控制基因组的分子机制 稳定性，提供基本知识，帮助制定针对由以下原因引起的疾病的治疗策略 基因组不稳定，如癌症。这个项目的目标是研究多糖基化是如何控制 细胞周期中两个关键的有丝分裂调节因子的重新定位：核仁沉默和核仁沉默调节因子 有丝分裂退出的关键时期)和染色体必需的CPC(染色体乘客复合体) 双极连接。我们最近发现，酵母细胞中的多糖基化诱导会触发这些蛋白的重新定位 两个关键的有丝分裂调节器。我们的初步数据支持多糖基化的中心假设 促进一些关键的有丝分裂调节因子的重新定位，以成功地启动后期，并激活Polo样蛋白 激酶通过磷酸化脱氨基酶来触发多聚糖基化。我们的目标将通过 具体目的如下：1)阐明核仁蛋白多糖基化的机制 促进有丝分裂退出的非局部化。2)确定CPC亚基的多糖基化如何促进CPC 易位。3)探讨细胞周期中多聚糖基化的时间调控机制。为了测试 为了实现我们的假设和目标，我们将结合萌芽酵母遗传学、细胞生物学和生物化学。 这项研究的成功完成将使我们全面了解多糖基化是如何 根据细胞周期控制蛋白质复合体的亚细胞定位。鉴于不同寻常的 相扑系统和细胞周期机制的保守性，在萌芽酵母中证明的原理是 极有可能转化为人类和其他真核生物。结果将对以下方面产生重要的积极影响 细胞生物学领域，因为它们将发现对基因组稳定至关重要的新机制，并揭示新的 癌症诊断和治疗的目标。