Molecular cytogenetic insights into the ageing syndrome Hutchinson-Gilford Progeria (HGPS)

Corso, Chiara; Parry, Elizabeth M.; Faragher, R. G. A.; Seager, Anna L.; Green, M.H.L.; Parry, James M.

doi:10.1159/000085666

Cited by 15 publications

(13 citation statements)

References 53 publications

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“…Suppression of proliferation defects associated with progerin expression has not been reported previously, although investigators have found that hTERT expression will immortalize HGPS fibroblasts (Wallis et al, 2004;Corso et al, 2005;Huang et al, 2005). Because the suppressive effects of hTERT are apparent immediately after hTERT expression, we disfavor a model whereby enhanced telomere length is a primary determinant.…”

Section: Discussionmentioning

confidence: 81%

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Kudlow

Stanfel

Burtner

et al. 2008

MBoC

116

118

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization. INTRODUCTIONThe nuclear lamins are broadly expressed and constitute the only intermediate filament proteins localized to the nucleus (Smith et al., 2005;Bridger et al., 2007;Dechat et al., 2008). Given the ability of lamins to form stable polymers resulting from coiled-coil interactions, they have typically been ascribed a structural role in the nucleus (McKeon et al., 1986;Lammerding et al., 2004Lammerding et al., , 2006; however, a variety of regulatory roles have also been proposed (Spann et al., 1997;Spann et al., 2002;Frock et al., 2006;Ivorra et al., 2006;Nitta et al., 2006Nitta et al., , 2007Scaffidi and Misteli, 2008). The two classes of lamins, B-type and A-type (of which lamin A and lamin C are the most prominent), have different patterns of expression. Whereas, isoforms of lamin B are expressed in all cells throughout development, lamins A and C (lamin A/C) are not expressed early in development. Instead, their expression begins during midgestation and is most prominent in differentiating and terminally differentiated cells (Rober et al., 1989).Mutations in LMNA (encoding all A-type lamins) are associated with at least 12 different human genetic disorders (Kudlow et al., 2007). Of these, at least three have features reminiscent of premature aging. The most common LMNAassociated premature aging-like syndrome, Hutchinson-Gilford progeria syndrome (HGPS), is often caused by a single nucleotide change in exon 11 of the LMNA gene (Cao and Hegele, 2003;De Sandre-Giovannoli et al., 2003;Eriksson et al., 2003). This mutation, generally referred to as G608G, is silent with regard to the coded a...

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Section: Discussionmentioning

confidence: 81%

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Kudlow

Stanfel

Burtner

et al. 2008

MBoC

116

118

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“…Some reports indicate that hTERT-mediated cellular immortalization is possible in certain HGPS strains (34,44,45), while others have found that HGPS fibroblasts are resistant to hTERT immortalization (46,47). Moreover, hTERT does not protect against progerin-induced aberrant nuclear shape and DNA damage (48).…”

Section: Discussionmentioning

confidence: 99%

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Wheaton

Campuzano

et al. 2017

Molecular and Cellular Biology

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Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability, and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here we show that young cycling HGPS fibroblasts exhibit chronic DNA damage, primarily in S phase, as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA, altering its distribution away from replicating DNA in HGPS cells, leading to ␥H2AX formation, ATR activation, and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress, and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.KEYWORDS HGPS, progerin, senescence, aging, p53, telomere T he study of children with rare accelerated aging (progeria) syndromes has provided insight into the normal process of aging. Hutchinson-Gilford progeria syndrome (HGPS) is caused by a heterozygous, autosomal dominant mutation in LMNA (1), the gene that encodes lamin A, a key structural protein in the nuclear lamina. The lamina, a protein network that lines the inner nuclear membrane, provides structural support for the nucleus and is important for chromatin attachment, DNA replication, nuclear organization, and gene transcription in ways that are not completely understood. Farnesylation of prelamin A at the C terminus allows targeting to the inner nuclear membrane, where it is subsequently cleaved by the zinc metalloproteinase Zmpste24 to release mature lamin A into the lamina and nucleoplasm. In HGPS, the most common LMNA mutation (G608G) activates a cryptic splice donor site in exon 11, resulting in prelamin A mRNA with a 150-bp internal deletion, leading to a 50-amino-acid truncation in a region that contains the Zmpste24 cleavage site (reviewed in reference 2). The mutant lamin, termed progerin, retains the farnesyl lipid anchor, interferes with the integrity of the nuclear lamina, and causes the formation of misshapen nuclei. The retention of progerin on the inner nuclear membrane interferes with the function and normal distribution of lamin A, causing a loss of peripheral heterochromatin, increased DNA damage, impaired recruitment of DNA repair proteins to sites of DNA damage (3), and persistent activation of DNA damage response proteins (4). In addition to its

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“…Mechanical weakening of vascular endothelial and smooth muscle cells could be the initiating pathological event that leads to arteriosclerosis (Davies, 1995;Mounkes & Stewart, 2004) or at least add to other cellular defects seen in HGPS such as genetic instability and premature cellular senescence (Mounkes & Stewart, 2004;Corso et al, 2005;Liu et al, 2005;Varela et al, 2005;Kudlow et al, 2007). Since vascular smooth muscle cells (VSCM) and endothelial cells were shown to be the primary targets of progerin build-up (McClintock et al, 2006) and are constantly exposed to fluid shear stress and strain in the vessel wall, increased cellular sensitivity to mechanical stress and impaired cell cycle activation may predominantly affect vascular cells and, therefore, contribute to arteriosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

et al. 2008

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SummaryHutchinson-Gilford progeria syndrome (HGPS), reportedly a model for normal aging, is a genetic disorder in children marked by dramatic signs suggestive for premature aging. It is usually caused by de novo mutations in the nuclear envelope protein lamin A. Lamins are essential to maintaining nuclear integrity, and loss of lamin A/C results in increased cellular sensitivity to mechanical strain and defective mechanotransduction signaling. Since increased mechanical sensitivity in vascular cells could contribute to loss of smooth muscle cells and the development of arteriosclerosis -the leading cause of death in HGPS patients -we investigated the effect of mechanical stress on cells from HGPS patients. We found that skin fibroblasts from HGPS patients developed progressively stiffer nuclei with increasing passage number. Importantly, fibroblasts from HGPS patients had decreased viability and increased apoptosis under repetitive mechanical strain, as well as attenuated wound healing, and these defects preceded changes in nuclear stiffness. Treating fibroblasts with farnesyltransferase inhibitors restored nuclear stiffness in HGPS cells and accelerated the wound healing response in HGPS and healthy control cells by increasing the directional persistence of migrating cells. However, farnesyltransferase inhibitors did not improve cellular sensitivity to mechanical strain. These data suggest that increased mechanical sensitivity in HGPS cells is unrelated to changes in nuclear stiffness and that increased biomechanical sensitivity could provide a potential mechanism for the progressive loss of vascular smooth muscle cells under physiological strain in HGPS patients.

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Molecular cytogenetic insights into the ageing syndrome Hutchinson-Gilford Progeria (HGPS)

Cited by 15 publications

References 53 publications

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

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