scholarly journals Farnesyltransferase inhibitor and rapamycin correct aberrant genome organisation and decrease DNA damage respectively, in Hutchinson–Gilford progeria syndrome fibroblasts

2018 ◽  
Vol 19 (6) ◽  
pp. 579-602 ◽  
Author(s):  
Mehmet U. Bikkul ◽  
Craig S. Clements ◽  
Lauren S. Godwin ◽  
Martin W. Goldberg ◽  
Ian R. Kill ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Organisation ◽  
Farnesyltransferase Inhibitor ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome

2012 ◽  
Vol 109 (41) ◽  
pp. 16666-16671 ◽  
Author(s):  
L. B. Gordon ◽  
M. E. Kleinman ◽  
D. T. Miller ◽  
D. S. Neuberg ◽  
A. Giobbie-Hurder ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Farnesyltransferase Inhibitor ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

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

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julio Aguado ◽  
Agustin Sola-Carvajal ◽  
Valeria Cancila ◽  
Gwladys Revêchon ◽  
Peh Fern Ong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Telomere Dysfunction ◽  
Damage Response ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractHutchinson–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.

scholarly journals Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7474
Author(s):  
Rouven Arnold ◽  
Elena Vehns ◽  
Hannah Randl ◽  
Karima Djabali
Keyword(s):  
De Novo ◽  
Early Death ◽  
Premature Aging ◽  
Farnesyltransferase Inhibitor ◽  
Cellular Toxicity ◽  
Signaling Axis ◽  
Cellular Stresses ◽  
Exon 11 ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called “progerin” that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.

scholarly journals Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

2017 ◽  
Vol 37 (14) ◽  
Author(s):  
Keith Wheaton ◽  
Denise Campuzano ◽  
Weili Ma ◽  
Michal Sheinis ◽  
Brandon Ho ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Stress ◽  
Lamin A ◽  
Premature Senescence ◽  
Replication Fork Progression ◽  
Damage Response ◽  
P53 Activation ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Replication Factors

ABSTRACT Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability, and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here we show that young cycling HGPS fibroblasts exhibit chronic DNA damage, primarily in S phase, as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA, altering its distribution away from replicating DNA in HGPS cells, leading to γH2AX formation, ATR activation, and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress, and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.

scholarly journals DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome

2011 ◽  
Vol 39 (6) ◽  
pp. 1764-1769 ◽  
Author(s):  
Phillip R. Musich ◽  
Yue Zou
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Severe Form ◽  
Premature Aging ◽  
Lamin A ◽  
Repair System ◽  
Group A ◽  
Fork Stalling ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson–Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.

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