Defining the mechanisms and consequences of noncanonical telomere functions

定义非规范端粒功能的机制和后果

• 批准号: 10419653
• 负责人: Julia Promisel Cooper
• 金额: $ 50.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419653
• 关键词: Address; Behavior; Binding; Biology; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cells; Centromere; Centrosome; Chromatin; Chromosomal Stability; Chromosomes; Complex; Conceptions; Fission Yeast; Foundations; Generations; Genetic; Genome; Genome Stability; Genomic Instability; Human; In Vitro; Interphase; Link; Malignant Neoplasms; Measures; Mediating; Meiosis; Microscopy; Mitotic; Mitotic Cell Cycle; Molecular; Nuclear; Nuclear Envelope; Nucleosomes; Pathway interactions; Phase; Phosphotransferases; Plasmids; Process; Proliferating; Property; Prophase; Proteins; Research; Role; SPO11 gene; Series; Skeleton; Textbooks; Work; Yeasts; base; cancer cell; chromatin remodeling; chromosome missegregation; cohesin; endonuclease; experimental study; frontier; in vivo; nuclear division; optogenetics; recruit; stem; telomere; telomere loss; tool; tumorigenesis

Abstract The canonical functions attributed to telomeres in textbooks are to protect chromosome ends from degradation and fusion, both of which are confirmed drivers of genome instability and tumorigenesis. We have discovered two new and unforeseen roles for telomeres that are crucial for safeguarding the genome. First, we found that by interacting during meiotic prophase with the LINC complex (linker of nucleo- and cyto-skeleton), which spans the nuclear envelope, telomeres promote the nuclear envelope breakdown needed for spindle formation and the meiotic nuclear divisions. Remarkably, centromeres perform this function analogously in mitotic cell cycles, and indeed sporadic contacts between centromeres and LINC during meiotic prophase can rescue the loss of telomere-LINC contacts, indicating a surprising instance of telomere-centromere interchangeability. What features of telomeres and centromeres endow them with the capacity to control nuclear envelope breakdown and therefore cell cycle progression? Here we propose a series of experiments to answer this question. Second, we found that by providing a nuclear microdomain conducive to centromere assembly, telomeres rescue a surprising tendency of centromeres to become dismantled upon meiotic onset by the very factors (the meiotic endonuclease Spo11 and the meiosis-specific cohesin Rec8) that define meiosis. Indeed, we found that expression of Spo11 or Rec8 (which are normally meiosis-specific) in proliferating cells induces centromere dismantlement and chromosome missegregation. Here we propose to determine the mechanisms of Spo11- and Rec8-mediated centromere dismantlement, how telomeres promote the reassembly of dismantled centromeres, and whether these observations are relevant to the growing list of human cancers that mis-express meiotic proteins. These studies will open up new frontiers by defining at the molecular level unanticipated features of two key lynchpins of chromosome stability, telomeres and centromeres.

抽象的 归因于教科书中端粒的规范功能是为了保护染色体末端 从降解和融合中，这两者都是确认的基因组不稳定性驱动因素和 肿瘤发生。我们已经发现了两个至关重要的新的且无法预料的角色 为了保护基因组。 首先，我们发现通过在减数分裂预言期间与林克综合体进行互动（接头 跨越核包膜的核和细胞骨架）促进了核的核 纺锤体形成和减数分裂核分裂所需的包膜分解。 值得注意的是，Centromeres在有丝分裂细胞周期中类似地执行此功能，实际上 减数分裂预言期间的丝粒和林之间的零星接触可以挽救损失 端粒 - 链接触点，表明端粒中心的一个令人惊讶的实例 互换性。端粒和中心粒的哪些特征赋予了它们能力 控制核包膜崩溃并因此，因此细胞周期的进展？在这里我们提出一个 一系列实验来回答这个问题。 其次，我们发现，通过提供有利于丝粒组装的核微域， Telomeres营救了一种令人惊讶的centromeres的趋势，即拆除减数分裂 发作是因素（减数分裂核酸内切酶SPO11和减数分裂特异性粘着蛋白 rec8）定义减数分裂。确实，我们发现Spo11或rec8的表达（它们是 通常在增殖细胞中特定于减数分裂特异 染色体错误分类。在这里，我们建议确定SPO11-和 REC8介导的丝粒拆除，端粒如何促进重新组装 拆除的中心粒，以及这些观察是否与日益增长的清单相关 人类癌症表达减数分裂蛋白。 这些研究将通过定义分子水平的意外来打开新的边界 染色体稳定性，端粒和丝粒的两个关键林奇宾的特征。