HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation
HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation
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HnRNP F/H 与 hTERC 和端粒酶全酶结合调节端粒酶功能并促进细胞增殖
DOI：
10.1038/s41418-019-0483-6
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Xu, Chenzhong;Xie, Nan;Chen, Jun
人类端粒酶RNA组分hTERC包括多个基序，这些基序有助于hTERC的生物发生、全酶活性和酶募集到端粒。hTERC在其5 '端含有几个鸟嘌呤束（g -束），但其相关蛋白及其在端粒酶功能中的潜在作用仍然知之甚少。异质核核糖核蛋白F、H1和H2 （hnRNP F/H）是优先结合多(G)-丰富序列RNA的剪接因子。在这里，我们证明hnRNP F/H与hTERC和端粒酶全酶结合来调节端粒酶的活性。我们在体外和体内发现hnRNP F/H与hTERC的5 '端区域结合，并鉴定出hTERC的前三个g区和hnRNP F/H的qRRM1结构域是它们相互作用所必需的。此外，hnRNP F/H还直接与端粒酶全酶相互作用。在功能上，我们发现hnRNP F/H在调节端粒酶活性和端粒长度中起重要作用。hnRNP F/H缺失严重影响肿瘤和干细胞增殖，诱导干细胞衰老，而过表达hnRNP F/H延缓干细胞衰老。总之，我们的发现揭示了hnRNP F/H作为hTERC和端粒酶全酶的结合伙伴调节端粒酶功能的新作用。
Human telomerase RNA component hTERC comprises multiple motifs that contribute to hTERC biogenesis, holoenzyme activity, and enzyme recruitment to telomeres. hTERC contains several guanine tracts (G-tracts) at its 5 '-end, but its associated proteins and potential roles in telomerase function are still poorly understood. The heterogeneous nuclear ribonucleoproteins F, H1, and H2 (hnRNP F/H) are splicing factors that preferentially bind to poly(G)-rich sequences RNA. Here, we demonstrate that hnRNP F/H associate with both hTERC and telomerase holoenzyme to regulate telomerase activity. We reveal hnRNP F/H bind to the 5 '-end region of hTERC in vitro and in vivo, and identify the first three G-tracts of hTERC and qRRM1 domain of hnRNP F/H are required for their interaction. Furthermore, hnRNP F/H also directly interact with telomerase holoenzyme. Functionally, we show that hnRNP F/H plays important roles in modulating telomerase activity and telomere length. Moreover, hnRNP F/H deletion greatly impair cancer and stem cell proliferation, and induce stem cell senescence, while hnRNP F/H overexpression delay stem cell senescence. Collectively, our findings unveil a novel role of hnRNP F/H as the binding partners of hTERC and telomerase holoenzyme to regulate telomerase function.