Dynamics of TERT regulation via alternative splicing in stem cells and cancer cells.
Dynamics of TERT regulation via alternative splicing in stem cells and cancer cells.
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DOI：
10.1371/journal.pone.0289327
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
端粒酶催化亚单位端粒酶逆转录酶（TERT）的选择性剪接（AS）是端粒酶活性调节的一部分。虽然癌细胞和体细胞之间存在端粒酶/TERT抑制的治疗窗口，但干细胞表达TERT并依赖端粒酶活性进行细胞的生理替代。因此，识别干细胞和癌细胞之间的TERT调节差异对于开发基于端粒酶抑制的癌症疗法以减少对干细胞的损伤是至关重要的。在这项研究中，我们测量了诱导多能干细胞（iPSC），神经祖细胞（NPC）和非小细胞肺癌细胞（NSCLC，Calu-6细胞）中的TERT剪接变体表达和端粒酶活性。我们观察到NOVA 1-PTBP 1-PTBP 2轴调节iPSC中的TERT选择性剪接（AS）及其向NPC的分化。我们还发现，剪接转换的端粒酶，调节端粒酶活性，是由不同的细胞密度诱导干细胞，而不是癌细胞。最后，我们确定了调节TERTAS的细胞类型特异性剪接因子。总的来说，我们的发现代表了理解干细胞和癌细胞中TERTAS调控的重要一步。
Part of the regulation of telomerase activity includes the alternative splicing (AS) of the catalytic subunit telomerase reverse transcriptase (TERT). Although a therapeutic window for telomerase/TERT inhibition exists between cancer cells and somatic cells, stem cells express TERT and rely on telomerase activity for physiological replacement of cells. Therefore, identifying differences in TERT regulation between stem cells and cancer cells is essential for developing telomerase inhibition-based cancer therapies that reduce damage to stem cells. In this study, we measured TERT splice variant expression and telomerase activity in induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and non-small cell lung cancer cells (NSCLC, Calu-6 cells). We observed that a NOVA1-PTBP1-PTBP2 axis regulates TERT alternative splicing (AS) in iPSCs and their differentiation into NPCs. We also found that splice-switching of TERT, which regulates telomerase activity, is induced by different cell densities in stem cells but not cancer cells. Lastly, we identified cell type-specific splicing factors that regulate TERT AS. Overall, our findings represent an important step forward in understanding the regulation of TERT AS in stem cells and cancer cells.
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影响因子：
64.8
作者：
Batista, Luis F. Z.;Pech, MatthewF.;Zhong, Franklin L.;Nguyen, Ha Nam;Xie, Kathleen T.;Zaug, Arthur J.;Crary, Sharon M.;Choi, Jinkuk;Sebastiano, Vittorio;Cherry, Athena;Giri, Neelam;Wernig, Marius;Alter, Blanche P.;Cech, Thomas R.;Savage, Sharon A.;Pera, Renee A. Reijo;Artandi, Steven E.
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影响因子：
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作者：
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通讯作者：
HARLEY, CB