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首页> 外文期刊>Philosophical Transactions of the Royal Society of London, Series B. Biological Sciences >Telomeres in cancer and ageing
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Telomeres in cancer and ageing

机译：癌症和老化的端粒

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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 telomerebinding 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.
机译：端粒保护染色体末端免受未安排的DNA修复和降解。端粒是由与专用蛋白阵列结合的重复DNA（TTAGGG重复）组成的异质结构域。端粒重复的长度和端粒突出蛋白的完整性对于端粒保护都很重要。此外，端粒长度和完整性受到许多表观遗传修饰的调节，从而指着对端粒函数的更高阶控制。在这方面，我们最近发现，端粒转录产生长，非编码RNA，其保持与端粒染色质有关，并且可能在端粒调节中具有重要作用。在过去，我们表明端粒酶的端粒长度和催化组分，是用于动员干细胞的关键决定因素。端粒酶和端粒长度对干细胞行为的这些影响预期端粒酶突变小鼠的过早衰老和癌症表型。最近，我们通过迫使通过增强癌症抗性的小鼠体系中的端粒酶表达来证明了端粒酶的抗衰老活性。避难所是与哺乳动物端粒结合的主要蛋白质复合物;然而，其对癌症和衰老的潜在相关性迄今为止仍未解决。为此，我们已经产生了针对避难蛋白TRF1，TPP1和RAP1有条定地删除的小鼠。这些小鼠的研究表明，即使端粒是正常长度的，也表明了端粒功能障碍，足以产生过早的组织变性，染色体畸变和肿瘤病变的引发。这些新的小鼠模型与端粒酶缺陷的小鼠模型一起是理解通过端粒功能障碍产生的人类病理的有价值的工具。

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