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

Author

Listed:
  • Valentina Buemi

    (Università degli Studi di Trieste
    The Institute of Cancer Research)

  • 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
    Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR))

  • 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
    Università degli Studi di Trieste)

  • Giannino Sal

    (Università degli Studi di Trieste
    IFOM Foundation-FIRC Institute of Molecular Oncology Foundation
    International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Stefan Schoeftner

    (Università degli Studi di Trieste)

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.

Suggested Citation

  • Valentina Buemi & Odessa Schillaci & Mariangela Santorsola & Deborah Bonazza & Pamela Veneziano Broccia & Annie Zappone & Cristina Bottin & Giulia Dell’Omo & Sylvie Kengne & Stefano Cacchione & Grazia, 2022. "TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29907-z
    DOI: 10.1038/s41467-022-29907-z
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    References listed on IDEAS

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    1. Robert L. Dilley & Priyanka Verma & Nam Woo Cho & Harrison D. Winters & Anne R. Wondisford & Roger A. Greenberg, 2016. "Break-induced telomere synthesis underlies alternative telomere maintenance," Nature, Nature, vol. 539(7627), pages 54-58, November.
    2. Rajika Arora & Yongwoo Lee & Harry Wischnewski & Catherine M. Brun & Tobias Schwarz & Claus M. Azzalin, 2014. "RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
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