Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, V6T 1Z3, Canada.
Squared Circle Group, Vancouver, British Columbia, V6T 1Z3, Canada.
Curr Top Med Chem. 2020;20(6):498-507. doi: 10.2174/1568026620666200131125110.
Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.
越来越多的端粒酶研究证据表明，除了其催化端粒重复合成活性外，端粒酶可能具有其他重要的生物学功能。端粒酶的典型作用是在端粒末端，它们延长端粒并维持基因组稳定性和细胞寿命。尽管存在端粒维持的替代机制（端粒延长或 ALT），但催化蛋白成分端粒酶逆转录酶（TERT）在癌细胞中优先高水平表达。TERT 的表达水平高于维持功能端粒长度所需的水平，这表明可能存在其他适应功能。TERT 的新兴非典型作用包括调节非端粒 DNA 损伤反应、促进细胞生长和增殖、加速细胞周期动力学以及氧化应激后控制线粒体完整性。TERT 的非典型活性主要表现出细胞保护作用，并且已经表明核 TERT 可以防止双链 DNA 损伤后的细胞死亡，而与其在端粒长度维持中的作用无关。TERT 被认为作为一种染色质调节剂，参与基因表达的转录调控。TERT 还被报道通过 RNA 依赖性 RNA 聚合酶（RdRP）活性调节转录本水平，并以依赖 Dicer 的方式产生 siRNAs。在线粒体中，TERT 被认为可以防止氧化应激诱导的 mtDNA 损伤并促进线粒体完整性。TERT 的这些非端粒功能在快速分裂的癌细胞中经常发现的增殖和代谢应激增加的情况下可能是有利的。了解端粒酶的非典型功能谱可能对合理设计抗癌化学治疗药物具有重要意义。
