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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Small-molecule-based identification of dynamic assembly of E2F-pocket protein-histone deacetylase complex for telomerase regulation in human cells.
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Small-molecule-based identification of dynamic assembly of E2F-pocket protein-histone deacetylase complex for telomerase regulation in human cells.

机译：基于小分子的E2F-口袋蛋白-组蛋白脱乙酰酶复合物动态组装的动态鉴定，用于调节人类细胞中的端粒酶。

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Activation of telomerase is crucial for cells to gain immortality. Most normal human somatic cells have a limited proliferative life span, and expression of the rate-limiting telomerase catalytic subunit, known as human telomerase reverse transcriptase (hTERT), has been believed to be tightly repressed. This model of hTERT regulation is challenged by the recent identification of the induction of hTERT in normal cycling human fibroblasts during their transit through S phase. Here we show the small-molecule-based identification of the assembly and disassembly of E2F-pocket protein-histone deacetylase (HDAC) complex as a key mechanistic basis for the repression and activation of hTERT in normal human cells. A cell-based chemical screen was used to identify a small molecule, CGK1026, that derepresses hTERT expression. CGK1026 inhibits the recruitment of HDAC into E2F-pocket protein complexes assembled on the hTERT promoter. Chromatin immunoprecipitation analysis reveals dynamic alterations in hTERT promoter occupancy by E2F and pocket proteins according to the cell cycle-dependent regulation of hTERT. Dominant-negative or protein-knockout strategies to disrupt the assembly of E2F-pocket protein-HDAC complex derepress hTERT and telomerase activity. Taken together with the results on the regulatory function of these complexes in cellular senescence and tumorigenesis, our findings suggest that dynamic assembly of E2F-pocket protein-HDAC complex plays a central role in the regulation of hTERT in a variety of proliferative conditions (e.g., normal cycling, senescent, and tumor cells).
机译：端粒酶的激活对于细胞获得永生至关重要。大多数正常的人体细胞具有有限的增殖寿命，并且据信紧密限制了限速端粒酶催化亚基的表达，称为人端粒酶逆转录酶（hTERT）。 hTERT调节的这种模型受到了最近鉴定的正常循环人成纤维细胞通过S期的过程中hTERT诱导的挑战。在这里，我们显示了基于小分子的E2F-口袋蛋白-组蛋白去乙酰化酶（HDAC）复合物的组装和拆卸鉴定，作为在正常人细胞中抑制和激活hTERT的关键机理基础。基于细胞的化学筛选被用于识别抑制hTERT表达的小分子CGK1026。 CGK1026抑制HDAC募集到组装在hTERT启动子上的E2F口袋蛋白复合物中。染色质免疫沉淀分析显示，根据hTERT的细胞周期依赖性调节，E2F和袋装蛋白在hTERT启动子占有率中发生了动态变化。显性阴性或蛋白质敲除策略破坏了E2F口袋蛋白-HDAC复合物的装配，降低了hTERT和端粒酶的活性。结合这些复合物在细胞衰老和肿瘤发生中的调控功能的结果，我们的发现表明，E2F-口袋蛋白-HDAC复合物的动态组装在多种增殖条件下（例如，正常的循环，衰老和肿瘤细胞）。

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