Primary laminopathy fibroblasts display altered genome organization and apoptosis

Meaburn, Karen J.; Cabuy, Erik; Bonne, Gisèle; Levy, Nicolas; Morris, Glenn E.; Novelli, Giuseppe; Kill, Ian R.; Bridger, Joanna M.

doi:10.1111/j.1474-9726.2007.00270.x

Cited by 132 publications

(177 citation statements)

References 83 publications

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“…It has been demonstrated that HGPS fibroblasts start acquiring a senescent phenotype at late passages (Columbaro et al, 2005; Goldman et al, 2004; Meaburn et al, 2007). We hypothesized that an altered response to stress stimuli could be a major determinant of cellular aging in those cells.…”

Section: Resultsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Resultsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…36 Interestingly, MADA cell homozygous the R527H mutation showed the highest rates of apoptosis and micronuclei formation compared to other MADA cell carrying different types of mutation in the lamin A gene. 7 Due to the connection of micronucleation with apoptosis and considering that apoptosis could potentially account for tissue degeneration in progeria, 37 it can be speculated that the high level of phosphorylated ATM and p53 in R527H MADA cells, is responsible for the high percentage of apoptotic cells and, consequently, for the senescent phenotype. 7 The p53-associated DNA damage repair pathway constitutes a complicated network.…”

Section: Discussionmentioning

confidence: 99%

“…7 Due to the connection of micronucleation with apoptosis and considering that apoptosis could potentially account for tissue degeneration in progeria, 37 it can be speculated that the high level of phosphorylated ATM and p53 in R527H MADA cells, is responsible for the high percentage of apoptotic cells and, consequently, for the senescent phenotype. 7 The p53-associated DNA damage repair pathway constitutes a complicated network. The CDKN1A gene and the GADD45 gene family have been reported to be downstream effectors of p53, required for cell cycle arrest following DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…1,5 Lamins are intermediate filament proteins and, as main components of the nuclear lamina, act as architectural element of the cell nucleus by forming an intracellular protein scaffold necessary to structurally support the nucleus, to organize chromatin, 6 and to control the correct chromosome positioning. 7 Some mutations in the human LMNA gene and all mutations in the human ZMPSTE24 gene, which encodes an endoprotease required for the proteolytic maturation of lamin A, 8 cause defective lamin A processing. This defect leads to three different laminopathic disorders, i.e., MADA, Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD), caused by prelamin A or by truncated forms of prelamin A accumulation, respectively.…”

Section: Introductionmentioning

confidence: 99%

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The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Masi¹,

D’Apice²,

Ricordy³

et al. 2008

Cell Cycle

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Mandibuloacral dysplasia type A (MADA; OMIM # 248370) is a premature ageing disease caused by the homozygous R527H mutation in the LMNA gene. At the cellular level, MADA is characterized by unprocessed prelamin A accumulation, nuclear architecture alterations, chromatin defects and increased incidence of apoptosis. In some progeroid laminopathies (e.g., HGPS) it has been demonstrated that such biochemical and morphological alterations are strongly linked with genomic instability. To test this also in MADA fibroblasts, their response to the ionising radiationinduced damage was analysed. We observed that their ability to repair the damage was significantly impaired, as demonstrated by the increased chromosome damage and the higher percentage of residual γ-H2AX foci, corresponding to unrepaired DNA-damage sites. Moreover, MADA fibroblasts showed a markedly reduced phosphorylation of p53 at Ser15(S15) and a lower induction of p53 and CDKN1A proteins after irradiation, compared to the control cell line. Upon irradiation, we also detected differences in the expression of some p53 downstream target genes. In addition, MADA cells showed partial defects in the checkpoint response, particularly in G 1 /S transition.Our results indicate that accumulation of the lamin A precursor protein determines a defect in DNA damage response after X-ray exposure, supporting a crucial role of lamin A in regulating DNA repair process and cell cycle control.

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“…This had widespread effects on gene expression patterns, including the upregulation of a 4 Mbp region on chromosome MMU18 (Malhas, et al 2007). Likewise, in cells derived from patients with laminopathies, a similar striking alteration in chromosome position was observed, supporting a role for lamins in controlling chromosome positioning and gene expression (Meaburn, et al 2007). …”

Section: Conservation Of Chromosome Positioning In Human and Mouse Numentioning

confidence: 62%

Position of human chromosomes is conserved in mouse nuclei indicating a species-independent mechanism for maintaining genome organization

et al. 2008

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The non-random positioning of chromosome territories in eukaryotic cells is largely correlated with gene density and is conserved throughout evolution. Gene rich chromosomes are predominantly central while gene poor chromosomes are peripherally localized in interphase nuclei. We previously demonstrated that artificially introduced human chromosomes assume a position equivalent to their endogenous homologues in the diploid colon cancer cell line DLD-1. These chromosomal aneuploidies result in a significant increase in transcript levels, suggesting a relationship between genomic copy number, gene expression and chromosome position. We previously proposed that each chromosome is marked by a "zip-code" that determines its non-random position in the nucleus. Here we investigated (1) whether mouse nuclei recognize such determinants of nuclear position on human chromosomes to facilitate their distinct partitioning and (2) if chromosome positioning and transcriptional activity remain coupled under these trans-species conditions. Using 3D-FISH, confocal microscopy and gene expression profiling, we show (i) that gene poor and gene rich human chromosomes maintain their divergent but conserved positions in mouse-human hybrid nuclei and (ii) that a foreign human chromosome is actively transcribed in mouse nuclei. Our results suggest a species-independent conserved mechanism for the non-random positioning of chromosomes in the 3-dimensional interphase nucleus.

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Primary laminopathy fibroblasts display altered genome organization and apoptosis

Cited by 132 publications

References 83 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

Position of human chromosomes is conserved in mouse nuclei indicating a species-independent mechanism for maintaining genome organization

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