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

Autor: Mehmet U. Bikkul, Joanna M. Bridger, Craig S. Clements, Lauren S. Godwin, Ian R. Kill, Martin W. Goldberg
Rok vydání: 2018
Předmět:
0301 basic medicine
Aging
congenital
hereditary
and neonatal diseases and abnormalities
Biology
medicine.disease_cause
Progeroid syndromes
Cell Line
LMNA
03 medical and health sciences
Progeria
Prenylation
Genome organisation
Farnesyltransferase inhibitors
medicine
Farnesyltranstransferase
Humans
Rapamycin
Insulin-Like Growth Factor I
Sirolimus
Mutation
Hutchinson–Gilford progeria syndrome
integumentary system
Diphosphonates
Genome
Human
Farnesyltransferase inhibitor
nutritional and metabolic diseases
Membrane Proteins
Metalloendopeptidases
Fibroblasts
medicine.disease
Progerin
Lamin Type A
Lamins
030104 developmental biology
COMET assay
Cancer research
DNA damage
Drug Therapy
Combination
Female
Geriatrics and Gerontology
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Gerontology
Protein Processing
Post-Translational
Lamin
Research Article
Zdroj: Biogerontology
Biogerontology, 2018, Vol.19(6), pp.579-602 [Peer Reviewed Journal]
ISSN: 1573-6768
Popis: 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 material The online version of this article (10.1007/s10522-018-9758-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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