Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
Nat Commun. 2022 Apr 28;13(1):2302. doi: 10.1038/s41467-022-29907-z.
Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.
目前尚不清楚哪些途径会引导癌细胞选择端粒酶依赖或基于重组的、替代性端粒延长（ALT）维持途径。本研究使用人类肺癌细胞和肿瘤类器官，结果表明，Trimethylguanosine Synthase 1（TGS1）在人类端粒酶 RNA 5'端形成 2,2,7-三甲基鸟苷（TMG）帽结构，对于招募端粒酶到端粒并使 Cajal 体参与端粒维持至关重要。TGS1 耗竭或天然核苷 sinefungin 的抑制作用会损害端粒酶向端粒的募集，导致外切核酸酶 1 介导的端粒 3'端突出的产生，这些突出与 RAD51 依赖性同源定向重组以及 ALT 途径的关键特征的激活相关。这表明 2,2,7-TMG 对人端粒酶（hTR）RNA 成分的加帽在执行端粒酶依赖性端粒维持中起着关键作用，以限制形成有利于 ALT 的端粒底物。我们的工作介绍了一种可靶向的端粒维持途径，该途径与端粒相关疾病（如癌症和衰老）有关。
