Dysfunction of lamin A triggers a DNA damage response and cellular senescence

Department of Biochemistry & Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alta., Canada T2N 4N1.
DNA Repair (Impact Factor: 3.11). 03/2006; 5(2):286-9. DOI: 10.1016/j.dnarep.2005.10.007
Source: PubMed


In higher eukaryotes, the nuclear lamins play an important role in maintaining the integrity of the nuclear envelope and the nucleus itself. Two recent papers show that a mutation that affects the processing of one of the nuclear lamins, lamin A, results in increased sensitivity to DNA damaging agents, an elevated DNA damage response, and a senescent phenotype. These studies underscore the role of the nuclear envelope in maintaining genomic stability and the interplay between nuclear architecture and the DNA damage response.

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    • "Lamin A is involved in regulation of gene expression in health and disease through interplay with cell cycle progression, DNA replication, signal transduction pathways, transcription factors, chromatin-associated proteins and tissue homeostasis (Andrés and González, 2009; Broers et al., 2006; Naetar and Foisner, 2009). Dysfunction of lamin A triggers DNA damage response, cellular senescence or apoptosis (Bridger and Kill, 2004; Lees-Miller, 2006; Musich and Zou, 2009). LMNA mutations cause a variety of human diseases termed laminopathies, including progeroid syndromes and premature-ageing disorders, e.g. "
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    ABSTRACT: Lamin A is an inner nuclear membrane protein that maintains nuclear structure integrity, is involved in transcription, DNA damage response and genomic stability, and also links to cell differentiation, senescence, premature aging and associated diseases. Induced pluripotent stem (iPS) cells have been successfully generated from various types of cells and used to model human diseases. It remains unclear whether levels of lamin A influence reprogramming of somatic cells to pluripotent states during iPS induction. Consistently, lamin A is expressed more in differentiated than in relatively undifferentiated somatic cells, and increases in expression levels with age. Somatic cells with various expression levels of lamin A differ in their dynamics and efficiency during iPS cell induction. Cells with higher levels of lamin A show slower reprogramming and decreased efficiency to iPS cells. Furthermore, depletion of lamin A by transient shRNA accelerates iPS cell induction from fibroblasts. Reduced levels of lamin A are associated with increased expression of pluripotent genes Oct4 and Nanog, and telomerase genes Tert and Terc. On the contrary, overexpression of lamin A retards somatic cell reprogramming to iPS-like colony formation. Our data suggest that levels of lamin A influence reprogramming of somatic cells to pluripotent stem cells and that artificial silencing of lamin A facilitates iPS cell induction. These findings may have implications in enhancing rejuvenation of senescent or older cells by iPS technology and manipulating lamin A levels.
    Biology Open 11/2012; 1(11):1118-27. DOI:10.1242/bio.20121586 · 2.42 Impact Factor
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    • "Among those most thoroughly investigated is the activation of DDR by telomere attrition which leads to cell cycle arrest termed replicative senescence (RS) or telomere-initiated CS [3-5]. Other well studied forms of CS include oncogene-induced senescence [6-8], cell structure induced senescence related to dysfunctional Lamin A [9], and stress-induced premature senescence (SIPS), the latter most thoroughly studied in relation to oxidative stress [10-12]. These various triggers of CS might not necessarily be mutually exclusive. "
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    ABSTRACT: Cellular senescence plays important roles in the aging process of complex organisms, in tumor suppression and in response to stress. Several markers can be used to identify senescent cells, of which the most widely used is the senescence-associated β-galactosidase (SABG) activity. The main advantage of SABG activity over other markers is the simplicity of the detection assay and the capacity to identify in situ a senescent cell in a heterogeneous cell population. Several approaches have been introduced to render the SABG assay quantitative. However none of these approaches to date has proven particularly amenable to quantitative analysis of SABG activity in situ. Furthermore the role of cellular senescence (CS) in vivo remains unclear mainly due to the ambiguity of current cellular markers in identifying CS of individual cells in tissues. In the current study we applied a digital image analysis technique to the staining generated using the original SABG assay, and demonstrate that this analysis is highly reproducible and sensitive to subtle differences in staining intensities resulting from diverse cellular senescence pathways in culture. We have further validated our method on mouse kidney samples with and without diabetes mellitus, and show that a more accurate quantitative SABG activity with a wider range of values can be achieved at a pH lower than that used in the conventional SABG assay. We conclude that quantitative in situ SABG assay, is feasible and reproducible and that the pH at which the reaction is performed should be tailored and chosen, depending on the research question and experimental system of interest.
    BMC Cell Biology 04/2011; 12(1):16. DOI:10.1186/1471-2121-12-16 · 2.34 Impact Factor
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    • "Lamins are type V intermediate filament proteins that have a role in nuclear mechanics and structure, chromatin organization, transcription, DNA replication, DNA damage response and genome stability [2] [12] [13]. They contain a characteristic central α-helical 'rod' domain flanked by globular N-terminal 'head' and C-terminal 'tail' domains. "
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    ABSTRACT: Lamins are major structural components of the lamina providing mechanical support for the nuclear envelope in vertebrates. A subgroup of lamins, the A-type lamins, are only expressed in differentiated cells and serve important functions both at the nuclear envelope and in the nucleoplasm in higher order chromatin organization and gene regulation. Mutations in A-type lamins cause a variety of diseases from muscular dystrophy and lipodystrophy to systemic diseases such as premature ageing syndromes. The molecular basis of these diseases is still unknown. Here we summarize known interactions of A-type lamins with components of the nuclear envelope and the nucleoplasm and discuss their potential involvement in the etiology and molecular mechanisms of the diseases. Lamin binding partners involve chromatin proteins potentially involved in higher order chromatin organization, transcriptional regulators controlling gene expression during cell cycle progression, differentiation and senescence, and several enzymes involved in a multitude of functions.
    Biochimica et Biophysica Acta 06/2007; 1773(5):661-74. DOI:10.1016/j.bbamcr.2006.07.002 · 4.66 Impact Factor
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