Abstract
In the premature ageing disease Hutchinson-Gilford progeria syndrome (HGPS), the underlying genetic defect in the lamin A gene leads to accumulation at the nuclear lamina of progerin—a mutant form of lamin A that cannot be correctly processed. This has been reported to result in defects in the DNA damage response and in DNA repair, leading to the hypothesis that, as in normal ageing and in other progeroid syndromes caused by mutation of genes of the DNA repair and DNA damage response pathways, increased DNA damage may be responsible for the premature ageing phenotypes in HGPS patients. However, this hypothesis is based upon the study of markers of the DNA damage response, rather than measurement of DNA damage per se or the consequences of unrepaired DNA damage—mutation. Here, using a mutation reporter cell line, we directly compared the inherent and induced mutation rates in cells expressing wild-type lamin A or progerin. We find no evidence for an elevated mutation rate in progerin-expressing cells. We conclude that the cellular defect in HGPS cells does not lie in the repair of DNA damage per se.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS) is a dominant severe premature ageing genetic disease characterised by the appearance in childhood of agerelated symptoms such as hair loss, thin skin, vascular defects and atherosclerosis
This leads to accumulation of lamin A protein lacking the 50 amino acid (a.a.) domain toward the C-terminus (LAΔ50/progerin) that is required for the final endoproteolytic cleavage step during the normal processing of prelamin A to lamin A
We find no significant elevation of the mutation rate, scored at the mutation reporter, in LAΔ50/progerin-expressing cells and suggest that underlying the cellular defect in HGPS cells does not lie in defective DNA repair per se
Summary
Hutchinson-Gilford progeria syndrome (HGPS) is a dominant severe premature ageing genetic disease characterised by the appearance in childhood of agerelated symptoms such as hair loss, thin skin, vascular defects and atherosclerosis. In the majority of cases, the underlying genetic defect is a point mutation that results in activation of a cryptic splice site in exon 11 of lamin A (LMNA) (Eriksson et al, 2003) This leads to accumulation of lamin A protein lacking the 50 amino acid (a.a.) domain toward the C-terminus (LAΔ50/progerin) that is required for the final endoproteolytic cleavage step during the normal processing of prelamin A to lamin A. Mutation of the FACE (Zmpste 24) metalloproteinase, which catalyses the final cleavage step of lamin A processing, results in restrictive dermopathy (RD) that has progeroid features (Navarro et al, 2004) It is the effect of the aberrantly farnesylated prelamin A proteins on nuclear architecture and nuclear function that is presumed to be responsible for the devastating phenotypes of these progeroid diseases (Mehta et al, 2011; Yang et al, 2011)
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