Aguado, J., Sola-Carvajal, A., Cancila, V. et al. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome. Nat Commun 10, 4990 (2019). https://doi.org/10.1038/s41467-019-13018-3
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
We thank Valentina Matti and Isabel Budenbender for technical help; Amanda Oldani and Sara Barozzi for providing assistance in image acquisition and analysis; Ylli Doksani for advice on telomere length assays; Ernst Wolvetang for support during the revision process of this paper; all F.d’A.d.F. laboratory members for discussions. J.A. was supported by Marie Curie Initial Training Networks (FP7 PEOPLE 2012 ITN (CodeAge
Project No: 316354)). F.d’A.d.F. was supported by the Associazione Italiana per la Ricerca sul Cancro, AIRC (application-12971 and 21091), Cariplo Foundation (grant-2014-0812), Fondazione Telethon (GGP17111), Progetti di Ricerca di Interesse Nazionale (PRIN) 2010-2011 and 2015, the Italian Ministry of Education Universities and Research EPIGEN Project, InterOmics Project and AMANDA project Accordo Quadro Regione
Lombardia–CNR, a European Research Council advanced grant (322726), AriSLA (project ‘DDRNA and ALS’) and AIRC Special Program 5 per mille metastases (Project21091). Research in the M.E. laboratory was supported by the Swedish Research Council and the Center for Innovative Medicine, Karolinska Institute.