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 教科书中端粒的典型功能是保护染色体末端 来自降解和融合，两者均被证实是基因组不稳定的驱动因素 肿瘤发生。我们发现了端粒的两个新的、不可预见的至关重要的作用 以保护基因组。 首先，我们发现通过在减数分裂前期与 LINC 复合体（ 核骨架和细胞骨架）跨越核膜，端粒促进核 纺锤体形成和减数分裂核分裂所需的包膜破裂。 值得注意的是，着丝粒在有丝分裂细胞周期中类似地执行此功能，并且确实 减数分裂前期着丝粒和 LINC 之间的零星接触可以挽救损失 端粒-LINC接触，表明端粒-着丝粒的一个令人惊讶的例子 互换性。端粒和着丝粒的哪些特征赋予它们能力 控制核膜破裂从而控制细胞周期进程？在这里我们提出一个 一系列的实验来回答这个问题。 其次，我们发现通过提供有利于着丝粒组装的核微域， 端粒拯救了着丝粒在减数分裂时被分解的令人惊讶的趋势 由多种因素（减数分裂核酸内切酶 Spo11 和减数分裂特异性粘连蛋白）引发 Rec8) 定义减数分裂。事实上，我们发现 Spo11 或 Rec8 的表达（它们是 通常减数分裂特异性）在增殖细胞中诱导着丝粒拆除并 染色体错误分离。在这里，我们建议确定 Spo11- 和 Rec8介导的着丝粒拆卸，端粒如何促进着丝粒的重组 拆除的着丝粒，以及这些观察结果是否与不断增长的列表有关 错误表达减数分裂蛋白的人类癌症。 这些研究将通过在分子水平上定义意想不到的方式开辟新的领域 染色体稳定性的两个关键关键——端粒和着丝粒的特征。