Chen Lu, Batista Luis Francisco Zirnberger
Cancer Signaling and Epigenetics Program and Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63110, USA
Cold Spring Harb Perspect Biol. 2025 Apr 10. doi: 10.1101/cshperspect.a041692.
Telomerase is a large ribonucleoprotein complex responsible for the addition of telomeric DNA repeats to chromosomal ends. Telomerase is composed of core and accessory components that work in coordination to ensure telomere length is maintained during development and in specific cell types. Telomerase activity is tightly regulated and is strongly increased in most tumor cells. On the other hand, loss-of-function mutations either in accessory factors or in core components of the complex impact telomere maintenance and cause a large spectrum of severe phenotypes, typically described as telomere biology disorders. A central element for efficient telomerase function is the proper biogenesis and assembly of the holoenzyme. Here, we discuss our current understanding of these processes and how they modulate telomerase efficiency. We consider how these processes are influenced by the specific subcellular localization of different telomerase components during different stages of the assembly of the holoenzyme. We describe the tremendous progress made in this area over the last decade and how recently discovered aspects of telomerase biogenesis can be exploited clinically, to actively benefit patients suffering from telomere biology disorders.
端粒酶是一种大型核糖核蛋白复合体，负责将端粒DNA重复序列添加到染色体末端。端粒酶由核心成分和辅助成分组成，它们协同工作以确保在发育过程中和特定细胞类型中端粒长度得以维持。端粒酶活性受到严格调控，在大多数肿瘤细胞中其活性会显著增加。另一方面，复合体辅助因子或核心成分的功能丧失突变会影响端粒维持，并导致一系列严重表型，通常被描述为端粒生物学紊乱。全酶的正确生物合成和组装是端粒酶高效发挥功能的核心要素。在此，我们讨论目前对这些过程的理解以及它们如何调节端粒酶效率。我们考虑在全酶组装的不同阶段，不同端粒酶成分的特定亚细胞定位如何影响这些过程。我们描述了过去十年在该领域取得的巨大进展，以及最近发现的端粒酶生物合成方面如何在临床上加以利用，从而切实造福患有端粒生物学紊乱的患者。
