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

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.

The Broad Spectrum of LMNA Cardiac Diseases: From Molecular Mechanisms to Clinical Phenotype

“…Consistently, chromatin remodeling and the associated transcriptional changes of disease-relevant genes, is also the prevalent model proposed for the HGPS, the most severe LMNAdependent disease (Goldman et al, 2004;Gordon et al, 2014;Aguado et al, 2019). Interestingly, a very recent study by Ikegami et al (2020) further contributed to the field describing a new regulatory mechanism by Lamin A/C.…”

The Role of Small Noncoding RNA in DNA Double-Strand Break Repair

“…Further study on a mouse model of HGPS indicated that the concentration of markers of DDR activation such as 53BP1 and ATM were higher compared to wild-type cells. Additionally, using telomeric sequence-specific ASOs, which block both-tDDRNAs and tdilncRNAs, inhibited DDR in telomeres providing further evidence for the regulation of 53BP1 foci formation via DDRNAs [84].…”

“…Interestingly, the production of DDRNs and their longer precursors have also been shown at telomeres. These sncRNAs are transcribed from both strands of deprotected telomeres, hence are called telomeric DDRNAs (tDDRNAs) and telomeric dilncRNAs (tdilncRNAs) [78,84,85]. Similarly, as in DDRNAs biogenesis, silencing of Dicer and Drosha fully abolished tDDRNA production while Drosha-knockdown lead to the accumulation of tdilncRNA [78], suggesting that both the proteins are crucial for tDDRNAs biosynthesis.…”

Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson–Gilford progeria (HGPS)

“…Upon reinitiating the cell cycle and entering S-phase (by plating the G0-arrested cells sparse), progerin-expressing cells accumulate DNA damage exclusively during the late stages of DNA replications, prior to chromosome condensation and mitosis, and preferentially in cells with low levels of heterochromatin [ 48 , 61–63 ]. Expression of hTERT, or modulation of the DDR specifically at telomeres, prevents (or rescues) progerin-induced DNA damage and senescence [ 23 , 48 , 58 , 79 , 85 ]. In somatic (hTERT-negative) cells, damaged telomeres cannot be repaired by conventional DNA repair processes and, thus, result in a permanent activation of DNA damage checkpoints and premature cellular senescence [ 23 , 40 , 48 , 58 , 86 ].…”