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.
Highlights
Alessandra Galati1, Livia Scatolini1, Emanuela Micheli1, Francesca Bavasso1, Alessandro Cicconi1, Paolo Maccallini1, Lu Chen2, Caitlin M
Prompted by our recent finding that mutations in trimethylguanosine synthase 1 (TGS1) increase the abundance of telomerase RNA and induce telomere elongation in living cells [33], we asked whether chemical inhibition of TGS1 activity could induce effects similar to those observed in TGS1 mutant cells
Our results clearly show that sinefungin inhibits the methyltransferase activity of TGS1, increases the human telomerase RNA (hTR) level, and promotes telomere elongation in both UMUC3 and HeLa cells, characterized by short and long telomeres, respectively
Summary
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. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Telomeres are specialized nucleoprotein structures at the extremities of linear chromosomes that serve at least two essential functions They hide chromosome ends from being recognized as DNA breaks, preventing DNA damage response and fusion between free chromosome ends [1]. Abbreviations AA, aplastic anemia; AdoMet, SAM, S-adenosylmethionine; DC, dyskeratosis congenita; GST, glutathione S-transferase; hTR, human telomerase RNA; PF, pulmonary fibrosis; TBD, telomere biology disorders; TGS1, trimethylguanosine synthase; TRAP assay, telomeric repeat amplification assay; TRF assay, telomere restriction fragment assay. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
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