Defining the mechanisms and consequences of noncanonical telomere functions

摘要 教科书中认为端粒的典型功能是保护染色体末端 从降解和融合，这两个都被证实是基因组不稳定和 肿瘤发生学。我们发现了端粒的两个新的、不可预见的角色，这两个角色是至关重要的 用来保护基因组。 首先，我们发现通过在减数分裂前期与LINC复合体(LINC的连接物)相互作用 核骨架)，它跨越核膜，端粒促进核 纺锤体形成和减数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执行这一功能类似，确实 着丝粒与LINC在减数分裂前期的零星接触可以挽救损失 端粒-LINC接触，这表明端粒-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 来控制核膜破裂，从而控制细胞周期进程？在这里，我们提出一种 用一系列实验来回答这个问题。 第二，我们发现通过提供有利于着丝粒组装的核微域， 端粒挽救了着丝粒在减数分裂中被拆解的惊人趋势 由特定因素(减数分裂内切酶Spo11和减数分裂特异粘附素)引起的 这是减数分裂的定义。事实上，我们发现了Spo11或Rec8(它们是 通常是减数分裂特异的)在增殖细胞中诱导着丝粒脱落和 染色体错误分离。在这里，我们建议确定Spo11-和 REC8介导的着丝粒拆除，端粒如何促进着丝粒重组 以及这些观察结果是否与越来越多的 错误表达减数分裂蛋白的人类癌症。 这些研究将开辟新的领域，在分子水平上定义意想不到的 染色体稳定的两个关键关键环节端粒和着丝粒的特征。

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.