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引用次数: 0
摘要
端粒是真核生物线性染色体末端的保护帽。端粒结合蛋白,包括称为 "庇护蛋白 "的复合体的六个组成部分,介导端粒的保护功能。它们通过抑制典型 DNA 损伤反应的许多环节来实现这一功能,从而防止端粒的不适当融合、切除和重组。其中一种方法是通过端粒促进DNA复制,从而防止 "复制压力 "反应和主激酶ATR的激活。另一方面,DNA损伤反应(包括复制应激和ATR)在端粒上发挥着积极作用,可触发端粒延长酶端粒酶的招募,从而抵消端粒的丢失。我们推测,端粒复制应激的抑制是端粒酶招募和端粒长度控制的共同机制,是包括TRF1、POT1和CTC1在内的几种核心端粒结合蛋白的共同机制。复制胁迫和 ATR 导致端粒酶招募的机制尚未完全阐明,但涉及作为受胁迫端粒锚的核肌动蛋白丝的形成。因此,核心端粒结合蛋白的突变导致端粒复制压力控制失调,可引起端粒长度控制失调,这是癌症和端粒生物学紊乱等疾病的特征。
Telomere maintenance and the DNA damage response: a paradoxical alliance.
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.
期刊介绍:
Frontiers in Cell and Developmental Biology is a broad-scope, interdisciplinary open-access journal, focusing on the fundamental processes of life, led by Prof Amanda Fisher and supported by a geographically diverse, high-quality editorial board.
The journal welcomes submissions on a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics, with sections focusing on signaling, adhesion, migration, cell death and survival and membrane trafficking. Additionally, the journal offers sections dedicated to the cutting edge of fundamental and translational research in molecular medicine and stem cell biology.
With a collaborative, rigorous and transparent peer-review, the journal produces the highest scientific quality in both fundamental and applied research, and advanced article level metrics measure the real-time impact and influence of each publication.