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RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

Author

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  • Rajika Arora

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

  • Yongwoo Lee

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

  • Harry Wischnewski

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

  • Catherine M. Brun

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

  • Tobias Schwarz

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

  • Claus M. Azzalin

    (Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ))

Abstract

A fraction of cancer cells maintain telomeres through the telomerase-independent, ‘Alternative Lengthening of Telomeres’ (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA–DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to telomeres specifically in ALT cells and its depletion led to telomeric hybrid accumulation, exposure of single-stranded telomeric DNA, activation of replication protein A at telomeres and abrupt telomere excision. Conversely, overexpression of RNaseH1 weakened the recombinogenic nature of ALT telomeres and led to telomere shortening. Altering cellular RNaseH1 levels did not perturb telomere homoeostasis in telomerase-positive cells. RNaseH1 maintains regulated levels of telomeric RNA–DNA hybrids at ALT telomeres to trigger HR without compromising telomere integrity too severely.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6220
    DOI: 10.1038/ncomms6220
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    Cited by:

    1. Francesc Muyas & Manuel José Gómez Rodriguez & Rita Cascão & Angela Afonso & Carolin M. Sauer & Claudia C. Faria & Isidro Cortés-Ciriano & Ignacio Flores, 2024. "The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Chia-Yu Guh & Hong-Jhih Shen & Liv WeiChien Chen & Pei-Chen Chiu & I-Hsin Liao & Chen-Chia Lo & Yunfei Chen & Yu-Hung Hsieh & Ting-Chia Chang & Chien-Ping Yen & Yi-Yun Chen & Tom Wei-Wu Chen & Liuh-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. 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.
    4. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Meng Xu & Dulmi Senanayaka & Rongwei Zhao & Tafadzwa Chigumira & Astha Tripathi & Jason Tones & Rachel M. Lackner & Anne R. Wondisford & Laurel N. Moneysmith & Alexander Hirschi & Sara Craig & Sahar A, 2024. "TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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