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.
Highlights
Genome organisationCell nuclei are the organelles that house an organisms’ genome
Since we have shown that small chromosome territories such as 18 are repositioned to the nuclear interior in nonproliferating cells (Bridger et al 2000; Mehta et al 2007, 2010a) it is imperative to combine the FISH with a marker for proliferation, such as staining for the nucleolar antigen Ki67
Mehta et al (2011) demonstrated that chromosome 18 is located in an interior position in interphase nuclei of senescent Hutchinson–Gilford progeria syndrome (HGPS) cells and it was revealed that after treatment with farnesyltransferase inhibitor (FTI)-277 alone and together with geranylgeranyltransferase inhibitors (GGTI)-2147, chromosome 18 was repositioned from an internal location to a peripheral one (Mehta et al 2011)
Summary
Genome organisationCell nuclei are the organelles that house an organisms’ genome. The chromosomes that make-up the genome are organised very with individual chromosomes located within their own individual space, the term ‘‘chromosome territories’’. Given all the processes the chromosomes have to go through, such as replication, transcription and repair, it is predictable that a system by which chromatin avoids being tangled up in the nucleus would evolve. This is regulated organisation at the intrachromosomal level but the cell takes this type of spatial organisation further to the interchromosomal level by regulating the specific locations of individual chromosomes radially with respect to the nuclear edge. The gene-density distribution of chromosomes is found in proliferating primary cells but when cells come out of the cell cycle into quiescence or senescence chromosomes are rearranged into a sizecorrelated distribution with large chromosomes at the nuclear periphery and small chromosomes in the nuclear interior (Bridger et al 2000; Mehta et al 2010a)
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