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.

TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance / Buemi, V.; Schillaci, O.; Santorsola, M.; Bonazza, D.; Broccia, P. V.; Zappone, A.; Bottin, C.; Dell'Omo, G.; Kengne, S.; Cacchione, S.; Raffa, G. D.; Piazza, S.; di Fagagna, F. A.; Benetti, R.; Cortale, M.; Zanconati, F.; Del Sal, G.; Schoeftner, S.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 13:1(2022), pp. 1-15. [10.1038/s41467-022-29907-z]

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

Cacchione S.;Raffa G. D.;
2022

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.
2022
Guanosine; Humans; RNA; Telomere; Telomerase
01 Pubblicazione su rivista::01a Articolo in rivista
TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance / Buemi, V.; Schillaci, O.; Santorsola, M.; Bonazza, D.; Broccia, P. V.; Zappone, A.; Bottin, C.; Dell'Omo, G.; Kengne, S.; Cacchione, S.; Raffa, G. D.; Piazza, S.; di Fagagna, F. A.; Benetti, R.; Cortale, M.; Zanconati, F.; Del Sal, G.; Schoeftner, S.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 13:1(2022), pp. 1-15. [10.1038/s41467-022-29907-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1634240
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