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化是一种重要的翻译后修饰，它增加了小的泛素样修饰物（SUMO）， 蛋白质赖氨酸残基。SUMO化调节许多细胞功能，包括细胞增殖，DNA修复， 和压力反应。SUMO化的失调导致基因组不稳定和癌症发展。 单个SUMO与蛋白质的连接通常会产生支架来使大分子相互作用成核。上 另一方面，SUMO链的连接（聚SUMO化）常常触发蛋白质泛素化和提取 从一个大分子复合体中分离出来。最近的工作表明了受损DNA的聚SUMO依赖性重新定位， 这有助于损伤修复。然而，蛋白质聚SUMO化的功能及其在细胞生长过程中的调控， 周期定义不明确。我们的长期目标是揭示控制基因组的分子机制 稳定性，以提供基础知识，这将有助于制定治疗战略， 基因组不稳定，如癌症。本项目的目的是研究聚SUMO化如何控制 细胞周期中两个关键的有丝分裂调节因子的重新定位：核仁沉默调节因子和 有丝分裂退出的关键），和CPC（染色体乘客复合物），染色体必需的 双极型依恋我们最近发现，酵母细胞中的聚SUMO化诱导触发了这些 两个重要的有丝分裂调节因子我们的初步数据支持中心假设，聚SUMO化 促进一些关键的有丝分裂调控成功的后期启动，并激活polo样 激酶通过磷酸化去SUMO酶触发聚SUMO化。我们的目标将通过 具体目的如下：1）阐明多聚SUMO化触发核仁蛋白的机制 促进有丝分裂退出的离域。2)确定CPC亚基的聚SUMO化如何促进CPC 易位3)研究细胞周期中polySUMO化的时间控制机制。测试 我们的假设和实现我们的目标，我们将结合联合收割机芽殖酵母遗传学，细胞生物学和生物化学。 这项研究的成功完成将提供一个全面的了解如何polySUMO化 在细胞周期中控制蛋白质复合物的亚细胞定位。鉴于特殊的 SUMO系统和细胞周期机制的保守性，在芽殖酵母中证明的原则是 很有可能翻译给人类和其他真核生物。其结果将产生重要的积极影响， 细胞生物学领域，因为他们将揭示基因组稳定性的新机制，并揭示新的 用于癌症诊断和治疗的靶点。