Abstract
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke. The most common mutation in HGPS is at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, producing a truncated farnesylated protein called progerin. Lamins play important roles in the organization and structure of the nucleus. The nuclear build-up of progerin causes severe morphological and functional changes in interphase HGPS cells. In this study, we investigated whether progerin elicits spatiotemporal deviations in mitotic processes in HGPS fibroblasts. We analyzed the nuclear distribution of endogenous progerin during mitosis in relation to components of the nuclear lamina, nuclear envelope (NE) and nuclear pores. We found that progerin caused defects in chromosome segregation as early as metaphase, delayed NE reformation and trapped lamina components and inner NE proteins in the endoplasmic reticulum at the end of mitosis. Progerin displaced the centromere protein F (CENP-F) from metaphase chromosome kinetochores, which caused increased chromatin lagging, binucleated cells and genomic instability. This accumulation of progerin-dependent defects with each round of mitosis predisposes cells to premature senescence.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, sporadic genetic disorder with phenotypic features of premature aging [1]
To determine how progerin elicits phenotypic changes in HGPS fibroblasts during interphase, we investigated the spatiotemporal distribution of progerin during the different stages of mitosis in relation to distributions of the following proteins: A- and B-type lamins, the integral inner nuclear envelope (NE) proteins emerin and SUN1, nuclear pores, the endoplasmic reticulum (ER) marker calnexin, microtubules, DNA, and the centromeric proteins CENP-E and centromere protein F (CENP-F)
We investigated the effects of endogenous progerin on the dynamics of mitosis in unsynchronized HGPS fibroblast cultures
Summary
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, sporadic genetic disorder with phenotypic features of premature aging [1]. Initial studies of progerin localization during mitosis in HeLa-transfected cells have provided the following major findings: (1) the anchorage of progerin to the INM disrupts the normal nuclear envelope (NE) disassembly, leading to the accumulation of progerin-membrane aggregates during mitosis [19, 20]; (2) these cytoplasmic progerin aggregates are associated with the INM protein SUN1 [21]; and (3) progerin’s farnesyl moiety is partially responsible for these mitotic defects because blocking this protein modification using FTIs ameliorated these alterations [1921] These previous studies used HeLa cell models and could not analyze the dynamics of endogenous progerin distribution in HGPS patient cells. From the comparison between progerin distribution and components from the NE, nuclear pores, nuclear lamina, kinetochores, chromosomes, microtubules and endoplasmic reticulum, we discuss progerin-dependent mechanisms that may lead to increased levels of lagging chromatin, binucleated cells and genomic instability
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