Telomeres in cancer and ageing.
Telomeres in cancer and ageing.
复制标题
DOI：
10.1098/rstb.2010.0291
复制
发表时间：
2011-01-12
期刊：
影响因子：
--
通讯作者：
Blasco MA
中科院分区：
文献类型：
--
作者：
Donate LE;Blasco MA
端粒保护染色体末端免受非程序性DNA修复和降解。端粒是由与一系列特化蛋白质结合的重复DNA（TTAGGG重复序列）组成的异染色质结构域。端粒重复序列的长度和端粒结合蛋白的完整性对端粒保护都很重要。此外，端粒的长度和完整性受到许多表观遗传修饰的调节，从而指向端粒功能的更高阶控制。在这方面，我们最近发现，端粒被转录产生长的非编码RNA，其保持与端粒染色质相关，并且可能在端粒调节中具有重要作用。在过去，我们发现端粒长度和端粒酶的催化成分Tert是干细胞动员的关键决定因素。端粒酶和端粒长度对干细胞行为的这些影响预测了端粒酶突变小鼠的过早衰老和癌症表型。最近，我们通过在具有增强的癌症抗性的小鼠中强制端粒酶表达来证明端粒酶的抗衰老活性。Shelterin是与哺乳动物端粒结合的主要蛋白质复合物;然而，其与癌症和衰老的潜在相关性迄今仍未得到解决。为此，我们产生了条件性缺失shelterin蛋白TRF 1、TPP 1和Rap 1的小鼠。对这些小鼠的研究表明，端粒功能障碍，即使端粒是正常长度的，也足以产生过早的组织变性、染色体畸变的获得和肿瘤病变的开始。这些新的小鼠模型，连同端粒酶缺陷的小鼠模型，是了解端粒功能障碍产生的人类病理学的有价值的工具。
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.
登录
查看更多内容
影响因子：
64.5
作者：
Sfeir A;Kosiyatrakul ST;Hockemeyer D;MacRae SL;Karlseder J;Schildkraut CL;de Lange T
通讯作者：
de Lange T
影响因子：
8
作者：
González-Suárez, E;Geserick, C;Blasco, MA
通讯作者：
Blasco, MA
影响因子：
11.4
作者：
Espejel, S;Franco, S;Blasco, MA
通讯作者：
Blasco, MA
影响因子：
3.7
作者：
Flores I;Blasco MA
通讯作者：
Blasco MA
影响因子：
64.8
作者：
Lee, HW;Blasco, MA;DePinho, RA
通讯作者：
DePinho, RA