TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance

Valentina Buemi, Odessa Schillaci, Mariangela Santorsola, Deborah Bonazza, Pamela Veneziano Broccia, Annie Zappone, Cristina Bottin, Giulia Dell’Omo, Sylvie Kengne, Stefano Cacchione, Grazia Daniela Raffa, Silvano Piazza, Fabrizio d’Adda Fagagna, Roberta Benetti, Maurizio Cortale, Fabrizio Zanconati, Giannino Sal and Stefan Schoeftner ()
Additional contact information
Valentina Buemi: Università degli Studi di Trieste
Odessa Schillaci: Università degli Studi di Trieste
Mariangela Santorsola: Università degli Studi di Trieste
Deborah Bonazza: Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) Trieste
Pamela Veneziano Broccia: Università degli Studi di Trieste
Annie Zappone: Università degli Studi di Trieste
Cristina Bottin: Università degli Studi di Trieste
Giulia Dell’Omo: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation
Sylvie Kengne: Università degli Studi di Trieste
Stefano Cacchione: Sapienza Università di Roma
Grazia Daniela Raffa: Sapienza Università di Roma
Silvano Piazza: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Fabrizio d’Adda Fagagna: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation
Roberta Benetti: Università degli Studi di Udine
Maurizio Cortale: Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) Trieste
Fabrizio Zanconati: Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) Trieste
Giannino Sal: Università degli Studi di Trieste
Stefan Schoeftner: Università degli Studi di Trieste

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5′ end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3′ end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.

Date: 2022
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DOI: 10.1038/s41467-022-29907-z

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