The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

Raz, Vered; Vermolen, Bart J.; Garini, Yuval; Onderwater, J. J. M.; Mommaas-Kienhuis, Mieke; Koster, Abraham J.; Young, Ian T.; Tanke, Hans J.; Dirks, Roeland W.

doi:10.1242/jcs.034876

Cited by 85 publications

(91 citation statements)

References 53 publications

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“…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%

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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: Resultscontrasting

confidence: 40%

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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“…The most prominent is formation of the senescence-associated heterochromatic foci [38]. Second is distorted organization of the nuclear lamina [5,39], such as downregulation of lamin B1 [40], which leads to the permeabilization of the nuclear envelope. It causes a loss of chromatin from the nucleus to the cytoplasm, together with a progressive decrease in histone content [41].…”

Section: Discussionmentioning

confidence: 99%

“…One of those changes is the accumulation of lysosomal enzyme β-galactosidase at pH = 6.0 (senescence-associated β-galactosidase/SA-β-Gal/SABG), whose activity is associated with cell senescence in vitro [3,4]. The process of cellular senescence refers to irreversible growth arrest, which is followed by changes in nuclear factors [5]. Although SA-β-Gal is widely used as a biomarker for detecting aging and senescence in stem cells in vitro [6], the proper identification of senescent cells is still insufficient and cell-based methods for identification of those cells are not quantitative [7].…”

Section: Introductionmentioning

confidence: 99%

Fractal and gray level co-occurrence matrix texture analysis of senescent and non-senescent deciduous teeth stem cells: A pilot study

Zaletel¹,

Milošević²,

Todorovic³

et al. 2016

Fractal Geometry and Nonlinear Anal in Med and Biol

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All cells in the human organism, including stem cells, have a limited lifespan and cease to divide after a certain number of divisions. The process of cellular senescence refers to incapability to progress through the cell cycle, thus leading the cell to an irreversible growth arrest. One of the most common biomarkers of cell senescence is senescence-associated β-galactosidase (SA-β-Gal/SABG), a lysosomal enzyme detectable at pH = 6.0. However, the proper identification of senescent cells is still insufficient and lacks adequate quantification parameters. In this paper we showed that fractal and gray level co-occurrence matrix (GLCM) texture analysis of cell nuclei are able to discriminate senescent from non-senescent cells. A total of 105 images of DTSCs nuclei from both SA-β-Gal+ and SA-β-Gal-cells were used in this study. All of the computed parameters (fractal dimension, angular second moment, inverse difference moment, contrast, entropy and correlation) showed significant statistical difference between the nuclei of senescent and non-senescent stem cells (p < 0.001). Our results show the possible practical value of fractal and GLCM texture analysis as the new markers in the determination and quantification of DTSCs senescence.

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“…This meticulous organization has functional relevance to the cell, assuring proper gene expression, replication, and genome stability (18). Diverse biological processes, such as DNA repair (19), senescence (20), apoptosis (21), and transformation (22) are associated with specific nuclear protein location patterns. Conversely, mislocalization of nuclear proteins, due to mutations, is associated with specific diseases, such as laminopathies, progeroid syndromes, and cancer (23,24).…”

mentioning

confidence: 99%

High content image cytometry in the context of subnuclear organization

et al. 2009

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The organization of proteins in space and time is essential to their function. To accurately quantify subcellular protein characteristics in a population of cells with regard for the stochasticity of events in a natural context, there is a fast-growing need for image-based cytometry. Simultaneously, the massive amount of data that is generated by image-cytometric analyses, calls for tools that enable pattern recognition and automated classification. In this article, we present a general approach for multivariate phenotypic profiling of individual cell nuclei and quantification of subnuclear spots using automated fluorescence mosaic microscopy, optimized image processing tools, and supervised classification. We demonstrate the efficiency of our analysis by determination of differential DNA damage repair patterns in response to genotoxic stress and radiation, and we show the potential of data mining in pinpointing specific phenotypes after transient transfection. The presented approach allowed for systematic analysis of subnuclear features in large image data sets and accurate classification of phenotypes at the level of the single cell. Consequently, this type of nuclear fingerprinting shows potential for high-throughput applications, such as functional protein assays or drug compound screening. ' 2009 International Society for Advancement of Cytometry

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The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

Cited by 85 publications

References 53 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

Fractal and gray level co-occurrence matrix texture analysis of senescent and non-senescent deciduous teeth stem cells: A pilot study

High content image cytometry in the context of subnuclear organization

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