IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139, Milan, Italy.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, QLD, 4072, Australia.
Nat Commun. 2019 Nov 18;10(1):4990. doi: 10.1038/s41467-019-13018-3.
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.
亨廷顿舞蹈病-早老综合征（HGPS）是一种以过早衰老特征为特征的遗传疾病。HGPS 患者的细胞表达早老素，这是一种缩短的核纤层蛋白 A 形式，会破坏细胞内稳态，导致核形状改变、基因组不稳定、异染色质丢失、端粒功能障碍和过早进入细胞衰老。最近，我们报道端粒功能障碍会诱导端粒非编码 RNA（tncRNA）的转录，从而控制功能失调端粒处的 DNA 损伤反应（DDR）。在这里，我们显示早老素诱导的端粒功能障碍会诱导 tncRNA 的转录。通过序列特异性端粒反义寡核苷酸（tASO）对其功能进行抑制，可以防止各种 HGPS 细胞系统（包括 HGPS 患者成纤维细胞）中完全 DDR 激活和过早的细胞衰老。我们还在体内显示，tASO 治疗可显著增强转基因 HGPS 小鼠模型中的皮肤内稳态和寿命。总之，我们的研究结果表明，端粒 DDR 激活在 HGPS 进行性早衰表型的体外和体内模型中具有重要作用。
