The S‐adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening. Issue 1 (5th December 2021)

• Record Type: Journal Article
• Authors: Galati, Alessandra; Scatolini, Livia; Micheli, Emanuela; Bavasso, Francesca; Cicconi, Alessandro; Maccallini, Paolo; Chen, Lu; Roake, Caitlin M.; Schoeftner, Stefan; Artandi, Steven E.; Gatti, Maurizio; Cacchione, Stefano; Raffa, Grazia D.
• Is Part Of: FEBS letters. Volume 596:Issue 1(2022)
• Page Start: 42
• Page End: 52
• Publication Date: 2021-12-05
• Subjects: hTR -- RNA methyltransferase -- RNA processing -- Sinefungin -- telomerase -- telomerase reverse transcriptase (TERT) -- telomere -- telomere biology disorders (TBDs) -- telomere lengthening -- TGS1; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1002/1873-3468.14240
• Languages: English
• ISSNs: 0014-5793

Abstract

Abstract : Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S‐adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels. Abstract : The trimethylguanosine synthase TGS1 negatively regulates the abundance of the telomerase RNA component hTR. We show that inhibition of TGS1 activity by the S‐adenosylmethionine analog sinefungin results in increased hTR levels and telomerase activity and consequent telomere lengthening. Our results suggest that pharmacological inhibition of TGS1 might represent a new strategy to treat short telomere syndromes.