Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction
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 lin...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721004964 |
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| author | Shalu Sharma Ananda Kishore Mukherjee Shuvra Shekhar Roy Sulochana Bagri Silje Lier Meenakshi Verma Antara Sengupta Manish Kumar Gaute Nesse Deo Prakash Pandey Shantanu Chowdhury |
| author_facet | Shalu Sharma Ananda Kishore Mukherjee Shuvra Shekhar Roy Sulochana Bagri Silje Lier Meenakshi Verma Antara Sengupta Manish Kumar Gaute Nesse Deo Prakash Pandey Shantanu Chowdhury |
| author_sort | Shalu Sharma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T04:55:19Z |
| format | Article |
| id | doaj.art-31ab0e244fa34537a9b0a97737a04c10 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T04:55:19Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-31ab0e244fa34537a9b0a97737a04c102022-12-21T22:02:44ZengElsevierCell Reports2211-12472021-05-01357109154Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interactionShalu Sharma0Ananda Kishore Mukherjee1Shuvra Shekhar Roy2Sulochana Bagri3Silje Lier4Meenakshi Verma5Antara Sengupta6Manish Kumar7Gaute Nesse8Deo Prakash Pandey9Shantanu Chowdhury10Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaDepartment of Microbiology, Oslo University Hospital, Oslo, Norway; Institute of Basic Medical Sciences, University of Oslo, Oslo, NorwayIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaImaging Facility, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, IndiaDepartment of Microbiology, Oslo University Hospital, Oslo, NorwayDepartment of Microbiology, Oslo University Hospital, Oslo, NorwayIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721004964telomerasetelomere repeat binding factorshelterin proteinscancerhTERT promoter mutationsG-quadruplexe |
| spellingShingle | Shalu Sharma Ananda Kishore Mukherjee Shuvra Shekhar Roy Sulochana Bagri Silje Lier Meenakshi Verma Antara Sengupta Manish Kumar Gaute Nesse Deo Prakash Pandey Shantanu Chowdhury Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction Cell Reports telomerase telomere repeat binding factor shelterin proteins cancer hTERT promoter mutations G-quadruplexe |
| title | Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction |
| title_full | Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction |
| title_fullStr | Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction |
| title_full_unstemmed | Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction |
| title_short | Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction |
| title_sort | human telomerase is directly regulated by non telomeric trf2 g quadruplex interaction |
| topic | telomerase telomere repeat binding factor shelterin proteins cancer hTERT promoter mutations G-quadruplexe |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721004964 |
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