Harman Ashley, Bryan Tracy M
Cell Biology Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, Australia.
Front Cell Dev Biol. 2024 Oct 17;12:1472906. doi: 10.3389/fcell.2024.1472906. eCollection 2024.
Telomeres are the protective caps at the ends of linear chromosomes of eukaryotic organisms. Telomere binding proteins, including the six components of the complex known as shelterin, mediate the protective function of telomeres. They do this by suppressing many arms of the canonical DNA damage response, thereby preventing inappropriate fusion, resection and recombination of telomeres. One way this is achieved is by facilitation of DNA replication through telomeres, thus protecting against a "replication stress" response and activation of the master kinase ATR. On the other hand, DNA damage responses, including replication stress and ATR, serve a positive role at telomeres, acting as a trigger for recruitment of the telomere-elongating enzyme telomerase to counteract telomere loss. We postulate that repression of telomeric replication stress is a shared mechanism of control of telomerase recruitment and telomere length, common to several core telomere binding proteins including TRF1, POT1 and CTC1. The mechanisms by which replication stress and ATR cause recruitment of telomerase are not fully elucidated, but involve formation of nuclear actin filaments that serve as anchors for stressed telomeres. Perturbed control of telomeric replication stress by mutations in core telomere binding proteins can therefore cause the deregulation of telomere length control characteristic of diseases such as cancer and telomere biology disorders.
端粒是真核生物线性染色体末端的保护帽。端粒结合蛋白,包括被称为遮蔽蛋白复合体的六个组分,介导端粒的保护功能。它们通过抑制经典DNA损伤反应的多个环节来实现这一点,从而防止端粒发生不适当的融合、切除和重组。实现这一目的的一种方式是促进DNA通过端粒进行复制,从而防止“复制应激”反应以及主激酶ATR的激活。另一方面,包括复制应激和ATR在内的DNA损伤反应在端粒处发挥着积极作用,作为招募端粒延长酶端粒酶以抵消端粒丢失的触发因素。我们推测,抑制端粒复制应激是控制端粒酶招募和端粒长度的一种共同机制,这一机制为包括TRF1、POT1和CTC1在内的几种核心端粒结合蛋白所共有。复制应激和ATR导致端粒酶招募的机制尚未完全阐明,但涉及核肌动蛋白丝的形成,这些核肌动蛋白丝作为应激端粒的锚定物。因此,核心端粒结合蛋白中的突变对端粒复制应激的干扰控制可导致端粒长度控制失调,这是癌症和端粒生物学紊乱等疾病的特征。
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