Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Huang, Shurong; Risques, Rosa Ana; Martin, George M.; Rabinovitch, Peter S.; Oshima, Junko

doi:10.1016/j.yexcr.2007.08.004

Cited by 116 publications

(103 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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

show abstract

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

View full text Add to dashboard Cite

show abstract

“…For example, it was reported that the expression of lamin A (E145K progeria mutation) induced the formation of blebs in the nuclear membrane in which lamin B1 was excluded. 30 Another studies show that deletion of lamin B1 increases the size of the Lamin A/C meshwork and induces the formation of lamin A/C-rich and lamin B2-deficient NE blebs 32 23,[33][34][35][36] In contrast with HGP fibroblasts, the telomere length in hematopoietic cells, which typically do not express lamin A, was within the normal range in different HGPS patients' samples. These results suggest that expression of mutant lamin A is necessary for telomere loss in HGPS.…”

Section: Lamin Levels Must Be Tightly Controlled For the Maintenance mentioning

confidence: 99%

“…The silencing of lamin A results in NSA and senescence. On the other hand, the overexpression of the full length wild-type cDNA results also in growth defects, dysmorphic nuclei and senescence, [21][22][23] however the picture is more complex due to maturation of the lamin A protein.…”

Section: Lamin Levels Must Be Tightly Controlled For the Maintenance mentioning

confidence: 99%

Oxydative stress alters nuclear shape through lamins dysregulation

Barascu

Chalony²,

Pennarun³

et al. 2012

Nucleus

View full text Add to dashboard Cite

“…Cells derived from HGPS patients, like cells derived from patients with other progeroid syndromes, have been reported to undergo premature senescence (Huang et al, 2005(Huang et al, , 2008. However, in the case of HGPS patient-derived cells, no isogenic and simultaneously derived control fibroblasts have been available for direct comparison.…”

Section: Long-term Culturing Of Mutant Lamin A-expressing Cellsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Cited by 116 publications

References 61 publications

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

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

Oxydative stress alters nuclear shape through lamins dysregulation

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

Contact Info

Product

Resources

About