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Functional characterization of the TERRA transcriptome at damaged telomeres

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  • Antonio Porro

    (Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences
    Swiss Institute for Experimental Cancer Research (ISREC) at EPFL
    Present address: Institute of Molecular Cancer Research, Winterthurerstrasse 190, University of Zürich, Switzerland, CH-8057 Zürich, Switzerland)

  • Sascha Feuerhahn

    (Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences
    Swiss Institute for Experimental Cancer Research (ISREC) at EPFL
    Present address: Institute of Molecular Cancer Research, Winterthurerstrasse 190, University of Zürich, Switzerland, CH-8057 Zürich, Switzerland)

  • Julien Delafontaine

    (Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences
    Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics)

  • Harold Riethman

    (The Wistar Institute)

  • Jacques Rougemont

    (Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences
    Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics)

  • Joachim Lingner

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

Abstract

Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and demonstrate that TERRA upregulation is occurring upon depletion of TRF2 at all transcribed telomeres. TRF2 represses TERRA transcription through its homodimerization domain, which was previously shown to induce chromatin compaction and to prevent the early steps of DDR activation. We show that TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions. Altogether our data elucidate the TERRA landscape and defines critical roles for this RNA in the telomeric DNA damage response.

Suggested Citation

  • Antonio Porro & Sascha Feuerhahn & Julien Delafontaine & Harold Riethman & Jacques Rougemont & Joachim Lingner, 2014. "Functional characterization of the TERRA transcriptome at damaged telomeres," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6379
    DOI: 10.1038/ncomms6379
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    Cited by:

    1. Frances Karla Kusuma & Aishvaryaa Prabhu & Galen Tieo & Syed Moiz Ahmed & Pushkar Dakle & Wai Khang Yong & Elina Pathak & Vikas Madan & Yan Yi Jiang & Wai Leong Tam & Dennis Kappei & Peter Dröge & H. , 2023. "Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)," Nature Communications, Nature, vol. 14(1), pages 1-15, 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.

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