The S-adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening

FEBS Letters

article

Alessandra Galati¹  Livia Scatolini¹  Emanuela Micheli¹  Francesca Bavasso¹  Alessandro Cicconi¹  Paolo Maccallini¹  Lu Chen²  Caitlin M. Roake³  Stefan Schoeftner⁴  Steven E. Artandi³  Maurizio Gatti¹  Stefano Cacchione¹  Grazia D. Raffa¹ 

[1] Dipartimento di Biologia e Biotecnologie, Sapienza Università di Roma;Cancer Signaling and Epigenetics Program-Cancer Epigenetics Institute, Fox Chase Cancer Center;Department of Medicine, Stanford University School of Medicine;Dipartimento di Scienze della Vita, Università degli studi di Trieste;Istituto di Biologia e Patologia Molecolari del CNR

关键词: hTR;    RNA methyltransferase;    RNA processing;    Sinefungin;    telomerase;    telomerase reverse transcriptase (TERT);    telomere;    telomere biology disorders (TBDs);    telomere lengthening;    TGS1;   

DOI  :  10.1002/1873-3468.14240

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown