端粒维持研究进展

端粒是现代生物学的研究热点,与肿瘤发生、基因表达调控、衰老有着密切的关系。本综述介绍当前对端粒维持机理研究的进展。在端粒维持过程中有两类重要的蛋白：端粒相关蛋白和端粒酶。端粒相关蛋白是直接或间接与端粒结合的蛋白 ,在维持端粒稳定性方面有重要作用。端粒酶,特别是其催化亚基ｈＴＥＲＴ,在端粒延长过程中起着不可替代的作用,与细胞永生化和癌变密切相关。此外还介绍了在某些细胞中存在的不依赖端粒酶的端粒延长机     

端粒和端粒酶的发现及意义

端粒是真核生物染色体末端的一种特殊结构,对于维持染色体稳定性具有十分重要的意义,端粒长度的维持则需要端粒酶催化完成,端粒的长短和端粒酶的功能异常与细胞衰老和癌变有密切关联。回顾了端粒与端粒酶的发现历程及研究意义。     

端粒酶的非端粒保护作用

端粒酶与细胞永生化和肿瘤的发生发展密切相关,过去认为是由于端粒酶保护端粒从而阻止因端粒缩短所导致的细胞凋亡;然而近年来,越来越多证据表明:端粒酶在维持端粒长度之外,还存在着非端粒保护作用。通过对其非端粒保护作用的研究,有助于深入而全面地阐明端粒酶的生物学行为及其作用机理,对于肿瘤等疾病的治疗具有重要意义。本文对端粒酶的非端粒保护作用进行小结。     

依赖端粒酶的端粒维持机制

端粒是真核生物染色体的末端重要结构复合物,对维持染色体稳定性起着重要作用。端粒酶的主要功能是复制端粒末端DNA,维持端粒长度。端粒酶活性调节与肿瘤发生和细胞衰老有着密切关系。本简要综述近年来依赖端粒酶的端粒维持机理的研究进展。     

端粒酶线粒体转位

端粒酶是一种逆转录酶,主要存在于细胞核,其主要功能是维持端粒长度,有助于细胞永生化。现已发现,氧化应激可以改变端粒酶活性,促使端粒酶从细胞核转位到线粒体,因而不能继续维持端粒长度,使细胞端粒缩短。端粒酶线粒体转位的非依赖端粒功能包括改善线粒体功能、减少细胞氧化应激、拮抗细胞凋亡。     

染色体是如何被端粒和端粒酶保护的?——2009年诺贝尔生理学或医学奖解读

端粒对维持染色体的稳定和延长细胞寿命至关重要,其长度的维持有赖于端粒酶的存在.布莱克本和绍斯塔克发现端粒中的一种独特DNA序列能保护染色体免于退化,格雷德和布莱克本发现了端粒酶及其作用.这些发现揭示了端粒形成和端粒酶保护染色体的机理,3位美国科学家因此荣获2009年诺贝尔生理学或医学奖.     

鸡端粒酶RNA基因的克隆

本研究采用扩增条件优化的PCR扩增技术,以MDCC-MSBl细胞基因组DNA为模板扩增出鸡端粒酶RNA(chicken telomerase RNA,chTR)全长基因,克隆到pMD18-T载体中,经酶切鉴定和PCR鉴定后测定序列.序列分析表明所克隆的鸡端粒酶RNA基因全长465 bp,其中模板区的11个核苷(5'-CUAACCCUAAU-3')合成端粒亚单位(TTAGGG)n.chTR基因的克隆为进一步研究chTR在马立克氏病发病过程中的作用以及马立克氏病的发病机制提供可能的序列基础.     

端粒及端粒酶研究的最新进展

端粒是位于真核细胞染色体末端由重复DNA序列和蛋白组成的复合物,它具有保护染色体、介导染色体复制、引导减数分裂时的同源染爸体配对和调节细胞衰老等方面的作用。正常体细胞每分裂一代,端粒就会缩短一段,而端粒酶的作用是将一段端粒序列加到端粒末端,从而维持端粒长度。正常体细胞中是没有端粒酶活性的,而在大多数肿瘤细胞中都发现了端粒酶的表达,提示端粒和端粒酶在癌症发生和肿瘤细胞行为中具有重要作用。     

端粒-端粒酶系统与氧化还原微环境

端粒,作为染色体末端的特殊结构,可以有效保护染色体,防止其降解、末端融合和重组。端粒酶是通过逆转录维持端粒长度的蛋白核酸复合体。二者共同构成了端粒-端粒酶系统。经过近30年的研究,人们发现该系统与人类健康密切相关。氧化应激可导致端粒结构与功能的改变。本文总结了影响端粒、端粒酶结构与功能的不同途径,并分析了氧化还原微环境和氧化应激对其的影响及对人类疾病的作用。     

Ontogeny of telomerase in chicken: impact of downregulation on pre- and postnatal telomere length in vivo

Telomeres are the termini of linear chromosomes composed of tandem repeats of a conserved DNA sequence. Telomerase provides a mechanism for proliferating cells to offset telomeric sequence erosion by synthesizing new repeats onto the end of each parental DNA strand. Reduced or absent telomerase activity can lead to telomere shortening and genome instability. Telomeres and telomerase have not previously been characterized during ontogeny of any avian species. In the present study, telomerase activity in the chicken model was examined from early differentiation embryos through to adulthood. Telomerase activity was detected in all early embryos (preblastula through neurula) and in tissues throughout organogenesis. Subsequently, telomerase was downregulated in the majority of somatic tissues, either pre- or postnatally. A subset of tissues, such as intestine, immune and reproductive organs, exhibited constitutive activity. The impact of telomerase downregulation on telomere length was investigated and a telomere reduction of 3.2 kb in somatic tissues compared with germ line was observed in 5-year-old adults. The present results suggest that the telomere clock function is a conserved feature of avians as well as mammals. Knowledge regarding the relationships among telomerase regulation, proliferation/senescence profiles and differentiation status will be useful for numerous applications of chicken cells.     

哺乳动物早期胚胎端粒和端粒酶重编程

端粒位于真核染色体末端,是稳定染色体末端的重要元件。端粒酶(TER)是一种特殊的细胞核糖核蛋白(RNP)反转录酶(RT),其核心酶包括蛋白亚基和RNA元件。在DNA复制过程中的端粒丢失可以被有活性的端粒酶修复回来。哺乳动物端粒酶在发育中受调控,端粒的重编程可能是由于早期胚胎不同时期的端粒酶活性而造成的。因此,研究端粒和端粒酶重编程在早期胚胎发育中是非常重要的。该文综述了端粒和端粒酶的结构和功能,及其与哺乳动物早期胚胎发育的关系,并在此基础上展望了端粒和端粒酶在克隆动物胚胎发育的基础研究。     

动物克隆中的端粒和端粒酶

端粒是染色体上的一种重要结构,对维持染色体的稳定性起重要作用。核移植后,端粒长度和端粒酶活性的变化是重要的核重编程事件。不同种类的动物和供体细胞核移植后,在端粒长度的变化上存在一些差异,反映了重编程程度的不同。核移植后,在克隆囊胚中存在高水平的端粒酶活性,克隆动物的端粒长度延长,可能是由于克隆过程中端粒酶基因的重编程的缘故。     

Cell-cycle-dependent telomere elongation by telomerase in budding yeast

Telomeres are essential for the stability and complete replication of linear chromosomes. Telomere elongation by telomerase counteracts the telomere shortening due to the incomplete replication of chromosome ends by DNA polymerase. Telomere elongation is cell-cycle-regulated and coupled to DNA replication during S-phase. However, the molecular mechanisms that underlie such cell-cycle-dependent telomere elongation by telomerase remain largely unknown. Several aspects of telomere replication in budding yeast, including the modulation of telomere chromatin structure, telomere end processing, recruitment of telomere-binding proteins and telomerase complex to telomere as well as the coupling of DNA replication to telomere elongation during cell cycle progression will be discussed, and the potential roles of Cdk (cyclin-dependent kinase) in these processes will be illustrated.     

Telomeres in cancer and ageing

Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. Furthermore, telomere length and integrity are regulated by a number of epigenetic modifications, thus pointing to higher order control of telomere function. In this regard, we have recently discovered that telomeres are transcribed generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are likely to have important roles in telomere regulation. In the past, we showed that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of stem cells. These effects of telomerase and telomere length on stem cell behaviour anticipate the premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demonstrated the anti-ageing activity of telomerase by forcing telomerase expression in mice with augmented cancer resistance. Shelterin is the major protein complex bound to mammalian telomeres; however, its potential relevance for cancer and ageing remained unaddressed to date. To this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1 and Rap1. The study of these mice demonstrates that telomere dysfunction, even if telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions. These new mouse models, together with the telomerase-deficient mouse model, are valuable tools for understanding human pathologies produced by telomere dysfunction.     

端粒和端粒酶及其在肝细胞癌中的研究进展

摘要：端粒是位于染色体末端的特殊核蛋白复合物,其高度保守的重复序列和蛋白复合物形成保护环结构,以维持线性染色体的稳定性和完整性。端粒酶通过添加富含鸟嘌呤的重复序列,在维持和调节端粒长度、细胞永生性和衰老中起着重要作用。通过研究病变细胞的端粒长度变化趋势和端粒酶活性,可为选择端粒酶作为治疗癌症的标记物提供理论参考。本文针对端粒、端粒酶的结构和日常作用机理,以及它们在肝细胞癌中的研究进展进行综述,以期有助于恶性肿瘤和代谢性疾病的预防、诊断和治疗。     

Multiple facets of TPP1 in telomere maintenance

Telomeres are nucleoprotein complexes that cap the ends of all linear chromosomes and function to prevent aberrant repair and end-to-end chromosome fusions. In somatic cells, telomere shortening is a natural part of the aging process as it occurs with each round of cell division. In germ and stem cells, however, the enzyme telomerase synthesizes telomere DNA to counter-balance telomere shortening and help maintain cellular proliferation. Of the primary telomere end-binding proteins, TPP1 has recently emerged as a primary contributor in protecting telomere DNA and in recruiting telomerase to the telomere ends. In this review, we summarize the current knowledge regarding the role of TPP1 in telomere maintenance.     

Telomeric recombination induced by dysfunctional telomeres

Telomere maintenance is essential for cellular immortality, and most cancer cells maintain their telomeres through the enzyme telomerase. Telomeres and telomerase represent promising anticancer targets. However, 15% of cancer cells maintain their telomeres through alternative recombination-based mechanisms, and previous analyses showed that recombination-based telomere maintenance can be activated after telomerase inhibition. We determined whether telomeric recombination can also be promoted by telomere dysfunction. We report for the first time that telomeric recombination can be induced in human telomerase-positive cancer cells with dysfunctional telomeres.     

Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging

Telomeres are capping structures at the ends of eukaryotic chromosomes, which consist of repetitive DNA bound to an array of specialized proteins. Telomeres are part of the constitutive heterochromatin and are subjected to epigenetic modifications. The function of telomeres is to prevent chromosome ends from being detected as damaged DNA. Both the length of telomere repeats and the integrity of the telomere-binding proteins are important for telomere protection. Telomere length is regulated by telomerase, by the telomere-binding proteins, as well as by activities that modify the state of the chromatin. Various mouse models with altered levels of telomerase activity, or mutant for different telomere-binding proteins, have been recently generated. Here, I will discuss how these different mouse models have contributed to our understanding on the role of telomeres and telomerase in cancer and aging.     

一种含有端粒重复序列非编码RNA的发现及最新研究进展

端粒是染色体末端的特化结构,由简单呈串联线性排列的核酸重复序列及相关蛋白质组成。其核酸序列具有高度的保守性,均富含GC。在人类为TTAGGG的高度重复序列具有维持基因组完整性的作用。端粒功能异常会导致染色体失去稳定性,促进肿瘤的发生和发展。以往认为端粒附近区域不具有转录活性,但最近在Science杂志上Azzalin等首次报道了该区域可以转录一种非编码RNA,即端粒RNA(telomeric RNA)。该分子具有特殊的UUAGGG重复序列,在调控端粒长度和端粒酶活性上具有重要作用,在发育、衰老和肿瘤发生发展等研究中已成为热点。该文将对近期有关端粒RNA的研究进展予以综述。