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 and Fabrizio d’Adda di Fagagna ()
Additional contact information
Julio Aguado: IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13018-3

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