Welfer Griffin A, Freudenthal Bret D
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
University of Kansas Cancer Center, Kansas City, KS 66160, USA.
NAR Cancer. 2023 Mar 3;5(1):zcad010. doi: 10.1093/narcan/zcad010. eCollection 2023 Mar.
Telomerase is a specialized reverse transcriptase that synthesizes telomeric repeats at the ends of linear chromosomes. Telomerase is transiently expressed in germ and stem cells, but nearly all somatic cells silence it after differentiating. However, the vast majority of cancer cells reactivate and constitutively express telomerase to maintain replicative immortality. Because of this, telomerase has remained a promising broad-spectrum chemotherapeutic target for over 30 years. However, various challenges associated with obtaining high-resolution structural data for telomerase have limited the development of rationally designed structure-based therapeutics. Various techniques and model systems have been utilized to advance our understanding of the structural biology of telomerase. In particular, multiple high-resolution cryogenic electron microscopy (cryo-EM) structures published within the past few years have revealed new components of the telomerase complex with near atomic resolution structural models. Additionally, these structures have provided details for how telomerase is recruited to telomeres and its mechanism of telomere synthesis. With these new pieces of evidence, and the promising outlook for future refinements to our current models, the possibility of telomerase specific chemotherapeutics is becoming more tangible than ever. This review summarizes these recent advancements and outlines outstanding questions in the field.
端粒酶是一种特殊的逆转录酶，可在线性染色体末端合成端粒重复序列。端粒酶在生殖细胞和干细胞中短暂表达，但几乎所有体细胞在分化后都会使其沉默。然而，绝大多数癌细胞会重新激活并持续表达端粒酶以维持复制永生。因此，30多年来，端粒酶一直是一个有前景的广谱化疗靶点。然而，获取端粒酶高分辨率结构数据所面临的各种挑战限制了基于结构的合理设计疗法的发展。人们利用了各种技术和模型系统来加深我们对端粒酶结构生物学的理解。特别是，过去几年发表的多个高分辨率低温电子显微镜（cryo-EM）结构揭示了端粒酶复合物的新组分，并给出了近原子分辨率的结构模型。此外，这些结构还提供了端粒酶如何被招募到端粒以及其端粒合成机制的细节。有了这些新证据，以及对当前模型未来改进的乐观前景，端粒酶特异性化疗药物的可能性比以往任何时候都更加切实可行。本综述总结了这些最新进展，并概述了该领域悬而未决的问题。
