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

Claudio Tripodo, Peh Fern Ong, Agustin Sola-Carvajal, Francesca Rossiello, Gwladys Revêchon, Emelie Wallén Arzt, Corey Winston Jones-Weinert, Fabrizio D’Adda Di Fagagna, Julio Aguado, Maria Eriksson, Oliver Dreesen, Giovanna Lattanzi

Risultato della ricerca: Article

10 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)4990-
Numero di pagine11
RivistaNature Communications
Volume10
Stato di pubblicazionePublished - 2019

All Science Journal Classification (ASJC) codes

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

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    Tripodo, C., Ong, P. F., Sola-Carvajal, A., Rossiello, F., Revêchon, G., Wallén Arzt, E., Jones-Weinert, C. W., D’Adda Di Fagagna, F., Aguado, J., Eriksson, M., Dreesen, O., & Lattanzi, G. (2019). Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome. Nature Communications, 10, 4990-.