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

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal premature ageing disease in children. HGPS is one of several progeroid syndromes caused by mutations in the LMNA gene encoding the nuclear structural proteins lamins A and C. In classic HGPS the mutation G608G leads to the formation of a toxic lamin A protein called progerin. During post-translational processing progerin remains farnesylated owing to the mutation interfering with a step whereby the farnesyl moiety is removed by the enzyme ZMPSTE24. Permanent farnesylation of progerin is thought to be responsible for the proteins toxicity. Farnesyl is generated through the mevalonate pathway and three drugs that interfere with this pathway and hence the farnesylation of proteins have been administered to HGPS children in clinical trials. These are a farnesyltransferase inhibitor (FTI), statin and a bisphosphonate. Further experimental studies have revealed that other drugs such as N-acetyl cysteine, rapamycin and IGF-1 may be of use in treating HGPS through other pathways. We have shown previously that FTIs restore chromosome positioning in interphase HGPS nuclei. Mis-localisation of chromosomes could affect the cells ability to regulate proper genome function. Using nine different drug treatments representing drug regimes in the clinic we have shown that combinatorial treatments containing FTIs are most effective in restoring specific chromosome positioning towards the nuclear periphery and in tethering telomeres to the nucleoskeleton. On the other hand, rapamycin was found to be detrimental to telomere tethering, it was, nonetheless, the most effective at inducing DNA damage repair, as revealed by COMET analyses.Electronic supplementary materialThe online version of this article (10.1007/s10522-018-9758-4) contains supplementary material, which is available to authorized users.

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson‐Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform

“…In this study, we demonstrate for the first time that chromosome 18 territories are found in the nuclear interior of normal proliferating control cells, the only change being that they have been immortalized by hTERT. This interior location is also observed in the two immortalized HGPS cell lines and corresponds to that previously observed nuclear position for chromosome 18 territories in HGPS cells . Another novel finding of this study is that chromosome X territories are located in the nuclear interior in the T08 HGPS cell line.…”

“…This interior location is also observed in the two immortalized HGPS cell lines and corresponds to that previously observed nuclear position for chromosome 18 territories in HGPS cells. 40,66,71 Another novel finding of this study is that chromosome X territories are located in the nuclear interior in the T08 HGPS cell line. This line does not contain the classical G608G lamin A mutation and so does not express progerin, and displays lamin A expression (Supporting Information Figure S6).…”

“…Although, recent studies assessing the specific epigenetic clock DNA methylation markings of HGPS cells indicate that they have a prematurely aged signature . However, following treatment with farnesyl transferase inhibitors (FTIs), that prevent the farnesylation of proteins, leads to the mutant lamin A protein—progerin—to have no farnesylation moieties, and so does not become associated aberrantly with the nuclear envelope during mitosis, which restores chromosome territory to that of control cells …”

“…70 However, following treatment with farnesyl transferase inhibitors (FTIs), that prevent the farnesylation of proteins, leads to the mutant lamin A protein-progerin-to have no farnesylation moieties, and so does not become associated aberrantly with the nuclear envelope during mitosis, which restores chromosome territory to that of control cells. 66,71 In an effort to make HGPS cells more easily cultured and assayable, we employed cells that had been immortalized by hTERT. 72 A control hTERT normal fibroblast line was also employed.…”

The biology of ageing and the omics revolution

“…Rogers et al (2018) discuss the role of circadian clocks in adult stem cell maintenance and how they control stem cell function. The topic of therapeutics is continued by Bikkul's article which focuses on a rare premature ageing disease: Hutchinson-Gilford Progeria Syndrome (HGPS) and drug treatments and regimes currently used in clinical trials (Bikkul et al 2018). Finally, the review by Ezcurra (2018) discusses a new exciting research area in the field of ageing: how the human microbiome can change in specific disease states.…”