Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction
| Autor: | Shantanu Chowdhury, Antara Sengupta, Silje Lier, Meenakshi Verma, Manish Kumar, Shalu Sharma, Deo Prakash Pandey, Shuvra Shekhar Roy, Ananda Kishore Mukherjee, Gaute Nesse, Sulochana Bagri |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Telomerase Somatic cell QH301-705.5 cells G-quadruplex telomerase General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Humans cancer Neoplastic transformation Telomerase reverse transcriptase Biology (General) neoplasms telomere repeat binding factor G-quadruplexe biology EZH2 Telomere G-Quadruplexes shelterin proteins enzymes and coenzymes (carbohydrates) 030104 developmental biology hTERT promoter mutations embryonic structures biology.protein Cancer research biological phenomena cell phenomena and immunity PRC2 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 35, Iss 7, Pp 109154-(2021) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | Summary Human telomerase reverse transcriptase (hTERT) remains suppressed in most normal somatic cells. Resulting erosion of telomeres leads eventually to replicative senescence. Reactivation of hTERT maintains telomeres and triggers progression of >90% of cancers. However, any direct causal link between telomeres and telomerase regulation remains unclear. Here, we show that the telomere-repeat-binding-factor 2 (TRF2) binds hTERT promoter G-quadruplexes and recruits the polycomb-repressor EZH2/PRC2 complex. This is causal for H3K27 trimethylation at the hTERT promoter and represses hTERT in cancer as well as normal cells. Two highly recurrent hTERT promoter mutations found in many cancers, including ~83% glioblastoma multiforme, that are known to destabilize hTERT promoter G-quadruplexes, showed loss of TRF2 binding in patient-derived primary glioblastoma multiforme cells. Ligand-induced G-quadruplex stabilization restored TRF2 binding, H3K27-trimethylation, and hTERT re-suppression. These results uncover a mechanism of hTERT regulation through a telomeric factor, implicating telomere-telomerase molecular links important in neoplastic transformation, aging, and regenerative therapy. Graphic abstractSchematic representation of sample collection and analysis. The figure was created using BioRender.com |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|