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Merck
  • Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome.

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

Nature communications (2019-11-20)
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
초록

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.

MATERIALS
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Sigma-Aldrich
Anti-trimethyl-Histone H3 (Lys9) Antibody, clone 6F12-H4, clone 6F12-H4, from mouse
Sigma-Aldrich
Anti-TRF2 Antibody, clone 4A794, clone 4A794, Upstate®, from mouse
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, ascites fluid, clone B-5-1-2