IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-13018-3.html
   My bibliography  Save this article

Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

Author

Listed:
  • Julio Aguado

    (IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
    The University of Queensland)

  • Agustin Sola-Carvajal

    (Karolinska Institutet)

  • Valeria Cancila

    (University of Palermo)

  • Gwladys Revêchon

    (Karolinska Institutet)

  • Peh Fern Ong

    (Cell Ageing, Skin Research Institute Singapore)

  • Corey Winston Jones-Weinert

    (IFOM Foundation—FIRC Institute of Molecular Oncology Foundation)

  • Emelie Wallén Arzt

    (Karolinska Institutet)

  • Giovanna Lattanzi

    (Consiglio Nazionale delle Ricerche (IGM-CNR), Unit of Bologna
    IRCCS Istituto Ortopedico Rizzoli)

  • Oliver Dreesen

    (Cell Ageing, Skin Research Institute Singapore)

  • Claudio Tripodo

    (University of Palermo)

  • Francesca Rossiello

    (IFOM Foundation—FIRC Institute of Molecular Oncology Foundation)

  • Maria Eriksson

    (Karolinska Institutet)

  • Fabrizio d’Adda di Fagagna

    (IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
    Consiglio Nazionale delle Ricerche (IGM-CNR))

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

Suggested Citation

  • Julio Aguado & Agustin Sola-Carvajal & Valeria Cancila & Gwladys Revêchon & Peh Fern Ong & Corey Winston Jones-Weinert & Emelie Wallén Arzt & Giovanna Lattanzi & Oliver Dreesen & Claudio Tripodo & Fra, 2019. "Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13018-3
    DOI: 10.1038/s41467-019-13018-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-13018-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-019-13018-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. Daniel Whisenant & Kayeong Lim & Gwladys Revêchon & Haidong Yao & Martin O. Bergo & Piotr Machtel & Jin-Soo Kim & Maria Eriksson, 2022. "Transient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13018-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.