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: 10609069
• 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/10609069
• 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; Cytoskeleton; Endowment; Fission Yeast; Foundations; Generations; Genetic; Genome; Genome Stability; Genomic Instability; Human; In Vitro; Interphase; Link; Maintenance; Malignant Neoplasms; Measures; Mediating; Meiosis; Microscopy; Mitotic; Mitotic Cell Cycle; Molecular; Nuclear; Nuclear Envelope; Nucleosomes; Pathway interactions; Phase; Phosphotransferases; Plasmids; Process; Property; Prophase; Proteins; Research; Role; SPO11 gene; Series; Textbooks; Work; Yeasts; cancer cell; chromatin remodeling; chromosome missegregation; cohesin; endonuclease; experimental study; frontier; in vivo; nuclear division; optogenetics; recruit; stem; telomere; telomere loss; tool; transmission process; 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.

摘要 教科书中认为端粒的典型功能是保护染色体末端 降解和融合，这两者都是基因组不稳定性的驱动因素， 肿瘤发生我们已经发现了端粒的两个新的和不可预见的作用， 来保护基因组 首先，我们发现，通过在减数分裂前期与LINC复合物（LINC复合物的接头）相互作用， 细胞核和细胞骨架），它跨越核膜，端粒促进核 纺锤体形成和减数分裂核分裂所需的被膜破裂。 值得注意的是，着丝粒在有丝分裂细胞周期中类似地执行这一功能， 在减数分裂前期，着丝粒和LINC之间的零星接触可以挽救这种丢失 的端粒-LINC接触，表明一个令人惊讶的端粒-着丝粒 互换性.端粒和着丝粒的哪些特征赋予它们 来控制核膜的破裂进而控制细胞周期的进程在这里，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，通过提供一个有助于着丝粒组装的核微区， 端粒挽救了着丝粒在减数分裂时被拆除令人惊讶的趋势 正是由这些因素（减数分裂核酸内切酶Spo 11和减数分裂特异性粘蛋白）引起的 Rec 8）定义减数分裂。事实上，我们发现Spo 11或Rec 8的表达（ 通常是减数分裂特异性的）在增殖细胞中诱导着丝粒脱落， 染色体错误分离。在这里，我们建议确定Spo 11的机制， Rec 8介导的着丝粒重排，端粒如何促进重组， 被拆除的着丝粒，以及这些观察是否与越来越多的 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 染色体稳定性的两个关键关键点，端粒和着丝粒的特征。