Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
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DOI：
10.1186/s13073-016-0324-x
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发表时间：
2016-06-20
期刊：
影响因子：
12.3
通讯作者：
Shay JW
中科院分区：
文献类型：
--
作者：
Jafri MA;Ansari SA;Alqahtani MH;Shay JW
端粒在正常细胞中保持基因组的完整性，并且在连续的细胞分裂期间其进行性缩短诱导染色体不稳定性。在绝大多数癌细胞中，端粒长度由端粒酶维持。因此，端粒长度和端粒酶活性对于癌症的发生和肿瘤的存活至关重要。调控端粒长度的几种途径已经被确定，基因组规模的研究有助于定位参与端粒长度控制的基因。此外，对复发性人端粒酶基因hTERT启动子突变和参与端粒替代延长途径的基因（如ATRX和DAXX）突变的基因组筛选已经阐明了这些基因组变化如何有助于激活癌细胞中的端粒维持机制。也已经尝试开发基于端粒长度和端粒聚合酶的诊断工具和抗癌疗法。最近的努力揭示了端粒酶组装、细胞内运输和募集到端粒以完成DNA合成的关键方面，这可能为抗癌剂的开发提供新的靶点。本文就端粒的组织、功能及其在肿瘤发生中的作用作一综述。我们还强调了导致端粒酶重新激活的基因组突变，以及端粒酶重建和运输的机制，揭示了其在癌症发生和肿瘤发展中的功能。此外，端粒酶抑制剂的临床开发的最新进展，以及潜在的新的目标，将进行总结。
Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.