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 language | English |
|---|---|
| Article number | 4990 |
| Pages (from-to) | 1-11 |
| Number of pages | 11 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 1 2019 |
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Keywords
- Injections
- Steroids
- Peripheral nerves
- Radiology, interventional
- Ultrasonography
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome. / Aguado, Julio; Sola-Carvajal, Agustin; Cancila, Valeria; Revêchon, Gwladys; Ong, Peh Fern; Jones-Weinert, Corey Winston; Wallén Arzt, Emelie; Lattanzi, Giovanna; Dreesen, Oliver; Tripodo, Claudio; Rossiello, Francesca; Eriksson, Maria; d’Adda di Fagagna, Fabrizio.
In: Nature Communications, Vol. 10, No. 1, 4990, 01.12.2019, p. 1-11.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
AU - Aguado, Julio
AU - Sola-Carvajal, Agustin
AU - Cancila, Valeria
AU - Revêchon, Gwladys
AU - Ong, Peh Fern
AU - Jones-Weinert, Corey Winston
AU - Wallén Arzt, Emelie
AU - Lattanzi, Giovanna
AU - Dreesen, Oliver
AU - Tripodo, Claudio
AU - Rossiello, Francesca
AU - Eriksson, Maria
AU - d’Adda di Fagagna, Fabrizio
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Injections
KW - Steroids
KW - Peripheral nerves
KW - Radiology, interventional
KW - Ultrasonography
UR - http://www.scopus.com/inward/record.url?scp=85075114173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075114173&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13018-3
DO - 10.1038/s41467-019-13018-3
M3 - Article
C2 - 31740672
AN - SCOPUS:85075114173
VL - 10
SP - 1
EP - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4990
ER -