Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence

Benson, Erica K.; Lee, Sam W.; Aaronson, Stuart A.

doi:10.1242/jcs.067306

Cited by 160 publications

(165 citation statements)

References 65 publications

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“…We are unable to provide an explanation for this. A recent study reports that ectopic telomerase expression prevents progerin-induced proliferative defects, progerin-induced premature senescence, and progerin-induced DNA damage (49), consistent with previous reports (34,50). Telomerase, however, was unable to rescue two other progerininduced defects, namely, repression of the heterochromatic marker H3K27me3 and nuclear abnormalities.…”

Section: Discussionsupporting

confidence: 87%

“…While our findings suggest that telomere integrity is maintained in HGPS cells, other laboratories have reported that DNA damage occurs at telomeres during normal cellular senescence and during progerin-induced premature senescence (34,35). These findings are based on the presence of telomere aggregates that are associated with the nuclear lamina and with ␥H2AX foci.…”

Section: Resultscontrasting

confidence: 40%

“…Moreover, hTERT does not protect against progerin-induced aberrant nuclear shape and DNA damage (48). DNA damage at telomeres has been reported in cells undergoing replicative senescence and in cells undergoing progerin-induced premature senescence (34,35). In these studies, telomere dysfunction is reflected by the presence of telomere aggregates that are associated with the nuclear lamina and with ␥H2AX foci.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionsupporting

confidence: 87%

Section: Resultscontrasting

confidence: 40%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Impaired proliferation, increased senescence, and telomereassociated DNA damage that is rescued by hTERT have also been shown in cells expressing progerin, the truncated form of LMNA, which causes the premature aging syndrome HGPS (Kudlow et al, 2008;Benson et al, 2010). It remains unclear how increased LMNB1 expression or progerin independently results in growth arrest and cellular senescence.…”

Section: Sa--gal Stainingmentioning

confidence: 99%

Lamin B1 fluctuations have differential effects on cellular proliferation and senescence

Dreesen¹,

Chojnowski²,

Ong³

et al. 2013

J Exp Med

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Function of Proteins Identified as Part of the Nuclear Matrix

Zhang

Huo

Wen

2021

Encyclopedia of Life Sciences

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Nuclear matrix (NM) is an intranuclear protein network originally found after high‐salt or lithium diiodosalicylate extraction and nuclease treatment. Proteins identified as part of the NM comprise a multifunctional platform for various nuclear functions. NM contains proteins involved in chromatin packaging, deoxyribonucleic acid (DNA) replication, transcription, ribonucleic acid (RNA) splicing, DNA repair and cell signalling. Dysfunction of NM proteins may result in defective cell functions, abnormal organogenesis and disorders such as progeria and some cancers. Key Concepts Some NM proteins bind to chromatin via its scaffold/matrix‐attached regions (S/MARs), help chromatin loop formation or organise higher order chromatin architecture. The deoxyribonucleic acid (DNA) replication machinery can be attached to certain nuclear matrix (NM) proteins. Some NM proteins are associated with transcription factories and regulate gene expression. The abnormal expression or genetic variants of NM genes may cause development abnormalities and diseases.

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Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence

Cited by 160 publications

References 65 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

Lamin B1 fluctuations have differential effects on cellular proliferation and senescence

Function of Proteins Identified as Part of the Nuclear Matrix

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