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, Valentina
Conceptualization
;
Schillaci, Odessa
Methodology
;
Santorsola, Mariangela
Software
;
Bonazza, Deborah
Methodology
;
Zappone, Annie
Methodology
;
Bottin, Cristina
Methodology
;
Cortale, Maurizio
Membro del Collaboration Group
;
Zanconati, Fabrizio
Membro del Collaboration Group
;
Del Sal, Giannino
Membro del Collaboration Group
;
Schoeftner, Stefan
Conceptualization
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.
Pubblicato
https://www.nature.com/articles/s41467-022-29907-z
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050681/
File in questo prodotto:
File Dimensione Formato  
s41467-022-29907-z.pdf

accesso aperto

Tipologia: Documento in Versione Editoriale
Licenza: Creative commons
Dimensione 3.51 MB
Formato Adobe PDF
3.51 MB Adobe PDF Visualizza/Apri
41467_2022_29907_MOESM1_ESM.pdf

accesso aperto

Descrizione: Supplementary Information
Tipologia: Altro materiale allegato
Licenza: Creative commons
Dimensione 5.39 MB
Formato Adobe PDF
5.39 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/3019031
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? ND
social impact