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RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops

Author

Listed:
  • Marianna Feretzaki

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Michaela Pospisilova

    (Masaryk University)

  • Rita Valador Fernandes

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Thomas Lunardi

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Lumir Krejci

    (Masaryk University
    St Anne’s University Hospital)

  • Joachim Lingner

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

Abstract

Telomeres—repeated, noncoding nucleotide motifs and associated proteins that are found at the ends of eukaryotic chromosomes—mediate genome stability and determine cellular lifespan1. Telomeric-repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from chromosome ends2,3; these RNAs in turn regulate telomeric chromatin structure and telomere maintenance through the telomere-extending enzyme telomerase4–6 and homology-directed DNA repair7,8. The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system with which to dissect the underlying mechanisms, and show that the UUAGGG repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA–RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation trigger telomere fragility and are promoted by the recombinase RAD51 and its interacting partner BRCA2, but counteracted by the RNA-surveillance factors RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyses R-loop formation with TERRA in vitro, suggesting a direct involvement of this DNA recombinase in the recruitment of TERRA by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA-mediated R-loop formation after transcription, providing a mechanism for the recruitment of lncRNAs to new loci in trans.

Suggested Citation

  • Marianna Feretzaki & Michaela Pospisilova & Rita Valador Fernandes & Thomas Lunardi & Lumir Krejci & Joachim Lingner, 2020. "RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops," Nature, Nature, vol. 587(7833), pages 303-308, November.
  • Handle: RePEc:nat:nature:v:587:y:2020:i:7833:d:10.1038_s41586-020-2815-6
    DOI: 10.1038/s41586-020-2815-6
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    Cited by:

    1. 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.
    2. 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.
    3. Charles Bou-Nader & Ankur Bothra & David N. Garboczi & Stephen H. Leppla & Jinwei Zhang, 2022. "Structural basis of R-loop recognition by the S9.6 monoclonal antibody," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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