HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation

• Published in: Cell death and differentiation Vol. 27; no. 6; pp. 1998 - 2013
• Main Authors: Xu, Chenzhong, Xie, Nan, Su, Yuanyuan, Sun, Zhaomeng, Liang, Yao, Zhang, Na, Liu, Doudou, Jia, Shuqin, Xing, Xiaofang, Han, Limin, Li, Guodong, Tong, Tanjun, Chen, Jun
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2020; Nature Publishing Group UK
• Subjects: Binding Sites; Cell growth; Cell Proliferation; Guanine; HEK293 Cells; HeLa Cells; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Humans; Protein Binding; Ribonucleic acid; Ribonucleoproteins; RNA; RNA - metabolism; Senescence; Splicing factors; Stem cells; Telomerase; Telomerase - metabolism; Telomeres
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0483-6

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.