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

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, Francesca Rossiello, Maria Eriksson, Fabrizio d’Adda di Fagagna

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4990
Pages (from-to)1-11
Number of pages11
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • Injections
  • Steroids
  • Peripheral nerves
  • Radiology, interventional
  • Ultrasonography

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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