Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation
Summary: Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720300139 |
| _version_ | 1828423736171167744 |
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| author | Lu Chen Caitlin M. Roake Alessandra Galati Francesca Bavasso Emanuela Micheli Isabella Saggio Stefan Schoeftner Stefano Cacchione Maurizio Gatti Steven E. Artandi Grazia D. Raffa |
| author_facet | Lu Chen Caitlin M. Roake Alessandra Galati Francesca Bavasso Emanuela Micheli Isabella Saggio Stefan Schoeftner Stefano Cacchione Maurizio Gatti Steven E. Artandi Grazia D. Raffa |
| author_sort | Lu Chen |
| collection | DOAJ |
| description | Summary: Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation. : hTR, the RNA component of telomerase, acquires a trimethylguanosine cap synthesized by Trimethylguanosine synthase 1 (TGS1). Chen et al. show that TGS1 and cap hypermethylation control hTR abundance and intracellular distribution. Loss of TGS1 results in elevated hTR levels, increased telomerase activity and telomere elongation. Keywords: TGS1, hTR, TERT, telomerase, telomeres, cap hypermethylation, telomere elongation |
| first_indexed | 2024-12-10T16:07:09Z |
| format | Article |
| id | doaj.art-fb5097bebfa0486883060123f60f8335 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T16:07:09Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fb5097bebfa0486883060123f60f83352022-12-22T01:42:14ZengElsevierCell Reports2211-12472020-02-0130513581372.e5Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere ElongationLu Chen0Caitlin M. Roake1Alessandra Galati2Francesca Bavasso3Emanuela Micheli4Isabella Saggio5Stefan Schoeftner6Stefano Cacchione7Maurizio Gatti8Steven E. Artandi9Grazia D. Raffa10Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USADipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, ItalyDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, ItalyDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, ItalyDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, ItalyCancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, Trieste, ItalyDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, ItalyDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy; Istituto di Biologia e Patologia Molecolari (IBPM) del CNR, Roma, ItalyStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding authorDipartimento di Biologia e Biotecnologie, Sapienza Università di Roma, Roma, Italy; Corresponding authorSummary: Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation. : hTR, the RNA component of telomerase, acquires a trimethylguanosine cap synthesized by Trimethylguanosine synthase 1 (TGS1). Chen et al. show that TGS1 and cap hypermethylation control hTR abundance and intracellular distribution. Loss of TGS1 results in elevated hTR levels, increased telomerase activity and telomere elongation. Keywords: TGS1, hTR, TERT, telomerase, telomeres, cap hypermethylation, telomere elongationhttp://www.sciencedirect.com/science/article/pii/S2211124720300139 |
| spellingShingle | Lu Chen Caitlin M. Roake Alessandra Galati Francesca Bavasso Emanuela Micheli Isabella Saggio Stefan Schoeftner Stefano Cacchione Maurizio Gatti Steven E. Artandi Grazia D. Raffa Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation Cell Reports |
| title | Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation |
| title_full | Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation |
| title_fullStr | Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation |
| title_full_unstemmed | Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation |
| title_short | Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation |
| title_sort | loss of human tgs1 hypermethylase promotes increased telomerase rna and telomere elongation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720300139 |
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