文章：

端粒酶和端粒结合蛋白的端粒和外端粒作用

Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins

原文发布日期：2011-02-24

DOI: 10.1038/nrc3025

类型: Review Article

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要点：

1. Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence bound by a specialized six-protein complex known as shelterin, which has fundamental roles in the protection of chromosomes and the regulation of telomerase activity at chromosome ends. Excessive telomere shortening and severe telomere uncapping trigger a DNA damage response at chromosome ends, which are then recognized as double-strand breaks. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DNA damage response. Studies with mouse models that support a role for these proteins in cancer susceptibility and ageing-related pathologies are discussed in this Review.
2. Telomere dysfunction causes ageing and also constitutes a driving force for cellular transformation by causing genome instability. Molecular mechanisms underlying telomere-induced genomic instability are described.
3. Anti-ageing activity of telomerase has been demonstrated in mice overexpressing TERT genetically engineered to be cancer-resistant by means of enhanced expression of the p53, p16 and ARF tumour suppressors. Telomere-maintenance is the main mechanism underlying the anti-ageing phenotype of TERT-transgenic mice.
4. Telomere-independent functions of TERT have recently been described. Overexpression of TERT is a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity when in a complex with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP).
5. Roles for the shelterin component RAP1 beyond its roles in telomeres have been uncovered. Mammalian RAP1 is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as a essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway.
6. Telomerase and factors that influence its activity are very attractive targets for the treatment of degenerative diseases and cancer. TPP1 is involved in telomerase recruitment to telomeres. Drugs targeting TPP1 could certainly be a novel strategy for blocking the ultimate goal of telomerase, the lengthening of telomeres.

要点翻译：

1. 哺乳动物端粒由TTAGGG串联重复序列构成，这些序列与称为shelterin的特殊六蛋白复合体结合。该复合体在染色体保护及端粒酶活性调控中发挥重要作用。过度端粒缩短和严重端粒解帽会引发染色体末端的DNA损伤反应，使其被识别为双链断裂。根据DNA损伤反应的完整性，功能失调的端粒可导致癌症或衰老病理改变。本综述讨论了支持这些蛋白在癌症易感性和衰老相关病理中作用的啮齿动物模型研究。
2. 端粒功能障碍不仅引发衰老，还通过导致基因组不稳定性成为细胞转化的驱动力。本文阐述了端粒诱导基因组不稳定性的分子机制。
3. 在通过增强p53、p16和ARF肿瘤抑制因子表达而基因改造为抗癌的过表达TERT小鼠中，端粒酶的抗衰老活性得到证实。端粒维持是TERT转基因小鼠抗衰老表型的主要机制。
4. 近期研究发现TERT具有不依赖于端粒的功能。TERT过表达是Wnt-β-连环蛋白信号通路的转录调节因子，当与线粒体RNA加工内切核糖核酸酶（RMRP）的RNA组分形成复合物时，还具有RNA依赖性RNA聚合酶活性。
5. 研究发现shelterin组分RAP1在端粒之外也发挥作用。哺乳动物RAP1参与亚端粒区基因沉默和转录调控，并作为核因子-κB（NF-κB）介导通路的重要调节因子。
6. 端粒酶及其活性影响因子是治疗退行性疾病和癌症的极佳靶点。TPP1参与端粒酶向端粒的募集过程。靶向TPP1的药物无疑可成为阻断端粒酶最终目标（延长端粒）的新策略。

英文摘要：

Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division. Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends. Telomere elongation is carried out by telomerase. Telomerase can also act as a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR. This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites.

摘要翻译： 

哺乳动物端粒由TTAGGG序列的串联重复组成，随着细胞分裂次数增加而逐渐缩短。端粒保护需要维持一定长度的TTAGGG重复序列，以便 shelterin 蛋白复合体结合，从而阻止染色体末端激活DNA损伤应答（DDR）。端粒酶负责延长端粒。此外，端粒酶还可作为Wnt–β-catenin信号通路的转录调节因子，并具有RNA依赖的RNA聚合酶活性。端粒功能障碍可能导致癌症或衰老相关疾病，具体取决于DDR的完整性。本文综述了端粒相关蛋白通过调节端粒长度与保护，以及结合非端粒位点调控基因表达，在癌症与衰老中的作用。

原文链接：

Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins