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Cited by 120Nuclear Structure and FunctionDNA Repair MechanismsEffects of Radiation Exposure

Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A

Open access
Musich, Phillip R., Zou, Yue·2009·Aging
DOI 10.18632/aging.100012PMC PMC2765059
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Abstract

Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that in Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD), accumulation of progerin/FC-prelamin A disrupts replication and DNA damage responses, causing unrepairable DNA double-strand breaks (DSBs) and persistent ATM/ATR checkpoint activation. It highlights XPA mislocalization to laminopathy-induced DSBs as a mechanism that excludes DSB repair factors and silences nucleotide excision repair (NER), linking defective prelamin A maturation to genome instability.

Key findings

  • HGPS and RD cells accumulate DSBs with continued passage; γ-H2AX foci and phosphorylated Chk1, Chk2, and p53 increase, and ATM/ATR checkpoint pathways are persistently activated. Caffeine treatment or siRNA knockdown of ATM/ATR restores significant replicative activity in HGPS cells.
  • Rad50, Rad51, and 53BP1 fail to recruit to laminopathy-induced DSBs in HGPS and RD cells, while XPA colocalizes with γ-H2AX at these DSBs; XPC does not. XPA depletion partially restores Rad50, Rad51, and Ku70 recruitment to γ-H2AX chromatin and significantly reduces DSB levels in HGPS cells, but not CPT-induced DSBs in normal BJ cells.
  • Proposed mechanism: progerin/FC-lamin A sequester replication factors such as PCNA, polymerase δ, and RFC, leading to stalled replication forks that collapse into DSBs. XPA binds ds-ssDNA junctions at these sites, blocks DSB repair protein access, and traps the NER protein, which may explain UV hypersensitivity in progeroid cells.
  • Farnesyl transferase inhibitors (FTIs) correct nuclear dysmorphology but do not reduce DSB frequency or γ-H2AX levels; statins and amino-bisphosphonates appear more effective in model mice and cellular assays. HGPS individuals have an average life span of 13.5 years, while RD individuals suffer perinatal death.

Methods

  • Design: narrative review synthesizing recent findings on genomic instability and DNA damage responses in HGPS and RD.
  • Data/sample: discusses cultured HGPS and RD patient cells, normal BJ fibroblasts, Zmpste24-/- mouse embryonic fibroblasts and mouse bone marrow cells, HeLa cells transfected with progerin, and Zmpste24-/- mice.
  • Analysis: integrates results from cited immunofluorescence microscopy, chromatin immunoprecipitation (ChIP), neutral single-cell comet assays, Western blotting, siRNA knockdown, caffeine inhibition, and FTI treatment.

Limitations

  • The paper states outstanding questions remain: what causes XPA mislocalization to DSB sites, what is the epigenetic role of progerin in this process, and whether the same mechanism operates in normal aging.
  • Evident: as a narrative review, it reports no new primary data; conclusions depend on cited studies and a proposed model (Figure 3).
  • Evident: some cited observations are unpublished (e.g., PCNA foci in late-passage cells), and therapeutic discussion of statins/amino-bisphosphonates is forward-looking without clinical outcomes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.18632/aging.100012

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 132 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    PCNA foci were not seen in late-passage HGPS cells.

    “However, PCNA foci were not seen in late-passage cells (unpublished data)”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    As mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand breaks (DSBs).

    “As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs).”
    Quote in the paperSubstantial claim
  • Premisecitation

    DNA double-strand breaks accumulate in HGPS and RD cells.

    “While lamin A is not involved directly in DNA metabolism, particularly DNA repair and damage responses, DNA double-strand breaks (DSBs) are found to accumulate in HGPS and RD cells [18-20].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

    • cites [20] Misteli, 2005, Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome, Nat Med

      Not checked in the free run.

  • Premisecitation

    Zmpste24-/- MEFs are hypersensitive to UV irradiation, which typically induces bulky DNA adducts exclusively removed by the nucleotide excision repair pathway.

    “Interestingly, however, MEFs are also hypersensitive to UV irradiation which typically induces bulky DNA adducts exclusively removed by the nucleotide excision repair pathway (NER) [12].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

  • Interpretationreasoning

    In HGPS and RD cells, accessible DSB termini bind XPA, which excludes normal binding by DNA DSB repair proteins.

    “In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins.”
    Quote in the paperSubstantial claim
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    HGPS and RD are laminopathy-based diseases arising from mutations causing altered processing/maturation of lamin A, not from mutated DNA metabolism genes.

    “Interestingly, HGPS and RD are laminopathy-based diseases; they arise not from mutated DNA metabolism genes but from mutations causing altered processing/maturation of lamin A, an intermediate-filament protein component of the nuclear lamina [6,11-16].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [6] Monnat, 2007, Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases, Nat Rev Mol Cell Biol source

      Not checked in the free run.

    • cites [11] Collins, 2004, Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome, Proc Natl Acad Sci U S A

      Not checked in the free run.

    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

    • cites [13] Scaffidi, 2005, Genome instability in progeria: when repair gets old, Nat Med

      Not checked in the free run.

    • cites [14] Lévy, 2008, HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches, Mech Ageing Dev

      Not checked in the free run.

    • cites [15] Kennedy, 2005, A-type nuclear lamins, progerias and other degenerative disorders, Mech Ageing Dev

      Not checked in the free run.

    • cites [16] Gruenbaum, 2008, Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins, Proc Natl Acad Sci U S A

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    HGPS patients are heterozygous for a LMNA gene mutation, while RD individuals have a homozygous deficiency in the processing protease Zmpste24.

    “Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for a LMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During mitosis, progerin plus normal lamin A mis-localize into insoluble cytoplasmic aggregates and membranes, delaying their return to the INM and lamina of the reformed nucleus, causing spatial and functional disruption of interphase G1 chromatin and possibly bi-nucleate cells.

    “During mitosis progerin plus normal lamin A mis-localize into insoluble cytoplasmic aggregates and membranes, delaying their return to the INM and lamina of the reformed nucleus. This causes spatial and functional disruption of interphase G1 chromatin and may lead to formation of bi-nucleate cells [35,36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Goldman, 2007, Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging, Proc Natl Acad Sci U S A

      Not checked in the free run.

    • cites [36] Collins, 2007, A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells, Proc Natl Acad Sci U S A

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nucleoplasmic foci normally contain PCNA and polymerase δ and appear critical for ordered initiation of genome replication in early S-phase.

    “The nucleoplasmic foci normally contain the replicative proteins PCNA and polymerase δ and appear to be critical for ordered initiation of genome replication in early S-phase [32,33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Harlow, 2000, Nuclear organization of DNA replication in primary mammalian cells, Genes Dev

      Not checked in the free run.

    • cites [33] Kennedy, 2004, Nuclear reorganization of mammalian DNA synthesis prior to cell cycle exit, Mol Cell Biol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All Zmpste24 enzymatic activity is lost in RD; FC-prelamin A is toxic, especially with the absence of normal lamin A, causing perinatal death.

    “All Zmpste24 enzymatic activity is lost in individuals with RD (Zmpste24-/-); the farnesylated and carboxy-methylated prelamin A (FC-prelamin A) is toxic, especially with the absence of normal lamin A, causing perinatal death [29,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Levy, 2006, Molecular bases of progeroid syndromes, Hum Mol Genet source

      Not checked in the free run.

    • cites [30] Levy, 2004, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy, Hum Mol Genet

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    These mutations generate the mutant lamin A proteins progerin and FC-lamin A, which cause nuclear deformations and chromatin perturbations.

    “These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HGPS and RD are the most severe forms of progeria; HGPS individuals have an average life span of 13.5 years while RD individuals suffer perinatal death.

    “Nevertheless, HGPS and RD are the most severe forms of progeria; HGPS individuals have an average life span of 13.5 years while RD individuals suffer perinatal death [13,15,17].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Scaffidi, 2005, Genome instability in progeria: when repair gets old, Nat Med

      Not checked in the free run.

    • cites [15] Kennedy, 2005, A-type nuclear lamins, progerias and other degenerative disorders, Mech Ageing Dev

      Not checked in the free run.

    • cites [17] Misteli, 2005, The cell nucleus and aging: tantalizing clues and hopeful promises, PLoS Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    During interphase, HGPS/RD nuclei are lobulated, the nuclear lamina thickens, and there is a loss of heterochromatin and nucleoplasmic lamin A foci.

    “During interphase, the dysmorphic nuclei are lobulated, the nuclear lamina thickens, and there is a loss of heterochromatin and nucleoplasmic lamin A foci.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    HGPS individuals are heterozygous for a dominant LMNA mutation C1824T (G608G) that activates a cryptic splice donor, causing a 50-amino-acid deletion in prelamin A; mature lamin A is still largely produced.

    “The dominant mutation is a CàT base substitution at position 1824 within exon 11. Although there is no amino acid change (G608G) a cryptic splice donor site is activated within exon 11.”
    • Also stated in: § Laminopathies in Hutchinson-Gilford progeria syndrome & restrictive dermopathy · plain
      “Sporadic use of this cryptic site in splicing of LMNA pre-mRNA removes an additional 150 base-pair sequence, causing a 50-amino acid deletion (Figure 1) within the prelamin A protein though mature lamin A is still largely produced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Bound XPA signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth.

    “The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The missing region in progerin includes the second Zmpste24 cleavage site, so progerin is farnesylated and carboxy-methylated and accumulates, though slower than FC-prelamin A in RD.

    “The missing region includes the second Zmpste24 cleavage site (Figure 1). Thus, a slightly smaller farnesylated and carboxy-methylated mutant prelamin A protein (termed progerin or LAΔ50) forms and accumulates though at a much slower rate than for FC-prelamin A formed with the homozygous Zmpste24 mutation in RD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HGPS and RD cells accumulate DNA damage, in particular DSBs, with continued passage in culture, indicating that DNA repair activity is impaired in these cells.

    “Indeed, like other types of progeroid cells, HGPS and RD cells accumulate DNA damage, in particular DSBs, with continued passage in culture [12,18,19], indicating that DNA repair activity is impaired in these cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In HGPS/RD, histone modification and gene expression patterns change, and DNA damage increases with a loss of DNA repair efficiency.

    “Functionally, histone modification and gene expression patterns change [8,34], and DNA damage increases with a loss of DNA repair efficiency [12,18].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Bohr, 2005, Gene expression and DNA repair in progeroid syndromes and human aging, Ageing Res Rev source

      Not checked in the free run.

    • cites [34] Goldman, 2006, Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging, Proc Natl Acad Sci U S A

      Not checked in the free run.

    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The hydrophobic farnesyl chain gives progerin greater affinity for the inner nuclear membrane, redistributing progerin away from nucleoplasmic foci and deforming the membrane.

    “The hydrophobic farnesyl chain gives progerin a greater affinity for the inner nuclear membrane (INM), redistributing progerin away from nucleoplasmic foci. This association with the INM also deforms the membrane.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The DSB repair system per se in HGPS and RD cells is functional, and XPA behaves normally in not binding to genotoxin-induced DSBs.

    “The latter result demonstrates that the DSB repair system per se in HGPS and RD cells is functional, and, also that the XPA behaves normally in not binding to genotoxin-induced DSBs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    XPA binding to DNA DSBs in progeroid cells may explain the absence of appropriate repair proteins at these sites and the genome instability observed in these cells due to failure to execute DNA repair.

    “Thus, XPA binding to DNA DSBs in progeroid cells may explain the absence of appropriate repair proteins at these sites and the genome instability observed in these cells due to failure to execute DNA repair.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM and ATR cluster into distinct foci in nuclei of HGPS and RD cells, identical to those observed in BJ cells treated with UV irradiation (for ATR) or CPT (for ATM).

    “While ATM and ATR were diffusely distributed in the nuclei of BJ cells, they clustered into distinct foci in nuclei of the HGPS and RD cells [18]. These foci were identical to those observed in BJ cells treated with UV irradiation (for ATR) or CPT (for ATM) [12].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XPC does not exhibit nuclear foci in HGPS and RD cells, indicating that the colocalization of XPA and γ-H2AX is specific and not related to NER.

    “XPC is the major DNA damage recognition protein in NER [41] but did not exhibit nuclear foci in HGPS and RD cells indicating that the colocalization of XPA and γ-H2AX was specific and not related to NER [19].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Linn, 2004, Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints, Annu Rev Biochem

      Not checked in the free run.

    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XPA depletion significantly reduces the level of DSBs in HGPS cells but has no effect on CPT-induced DSB level in BJ cells.

    “This is further supported by their finding that XPA depletion significantly reduced the level of DSBs in HGPS cells but had no effect on CPT-induced DSB level in BJ cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In HGPS cells, nuclear γ-H2AX foci and DSB frequency increase in parallel relative to BJ fibroblasts, and cellular progerin levels exhibit similar increases.

    “Employing immunofluorescence tracking of γ-H2AX foci and neutral single-cell electrophoretic (comet) assays to measure DNA DSBs Zou's group observed a significant parallel increase in nuclear γ-H2AX foci and DSB frequency in HGPS cells relative to BJ fibroblasts. Cellular progerin levels exhibited similar increases in the aged progeroid cells [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microinjection of an N-terminal mutant lamin A protein (ΔNLA) disrupts nuclear lamina organization in mammalian cells and causes redistribution of the replication elongation proteins PCNA and RFC.

    “Microinjection of an N-terminal mutant lamin A protein (ΔNLA) disrupts the nuclear lamina organization in mammalian cells and causes a redistribution of the replication elongation proteins PCNA and RFC [57,58].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Goldman, 2000, Disruption of nuclear lamin organization blocks the elongation phase of DNA replication, J Cell Biol

      Not checked in the free run.

    • cites [58] Goldman, 1997, Disruption of nuclear lamin organization alters the distribution of replication factors and inhibits DNA synthesis, J Cell Biol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In HGPS and RD cells treated with CPT, XPA does not colocalize to CPT-induced DSBs, though it still colocalizes to endogenous laminopathy-induced DSB foci.

    “Furthermore, in HGPS and RD cells treated with CPT (a DSB-inducer) XPA did not colocalize to these CPT-induced DSBs though it still colocalized to the endogenous laminopathy-induced DSB foci.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HeLa cells transfected with a progerin-expressing plasmid exhibit ATR nuclear foci formation, demonstrating that foci formation is progerin-dependent.

    “It was observed that HeLa cells transfected with a progerin-expressing plasmid exhibited ATR nuclear foci formation, demonstrating that foci formation is progerin-dependent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Young HGPS and RD cells grow quite well but senesce quickly relative to normal fibroblasts and growth stops, much sooner for RD than HGPS.

    “Young HGPS and RD cells grow quite well but the cells senesce quickly relative to normal fibroblasts and growth stops, much sooner for RD than HGPS [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Histone H2AX is phosphorylated to γ-H2AX in response to DSBs in interphase cells via ATM signaling.

    “Histone H2AX is phosphorylated to γ-H2AX in response to DSBs in interphase cells via ATM signaling [39,40].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Iliakis, 2008, {gamma}-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin, Nucl Acids Res

      Not checked in the free run.

    • cites [40] Bonner, 1999, Megabase chromatin domains involved in DNA double-strand breaks in vivo, J Cell Biol

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    XPA is specifically needed for ATR signaling of DNA damage during S-phase, and XPA knockdown compromises the normal response to UV damage.

    “Bomgarden et al. found that of the multiple NER factors XPA specifically was needed for ATR signaling of DNA damage during S-phase and that XPA knockdown compromised the normal response to UV damage [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Cimprich, 2006, Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling, EMBO J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nuclease treatment of chromatin before immunoprecipitation releases XPA from the γ-H2AX chromatin complex, indicating that DNA mediates the association of XPA and γ-H2AX-marked chromatin containing DNA DSBs.

    “Nuclease treatment of the chromatin before immunoprecipitation released the XPA from the γ-H2AX chromatin complex. Thus, DNA mediates the association of XPA and γ-H2AX-marked chromatin containing DNA DSBs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As growth rate slows, the frequency of dysmorphic nuclei increases as does the number with γ-H2AX foci in HGPS/RD cells.

    “As the growth rate slows the frequency of dysmorphic nuclei increases as does the number with γ-H2AX (a marker of DNA DSBs) foci detected by immunofluorescence microscopy [11,19,37].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Collins, 2004, Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome, Proc Natl Acad Sci U S A

      Not checked in the free run.

    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

    • cites [37] Bonner, 2008, Delayed kinetics of DNA double-strand break processing in normal and pathological aging, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caffeine treatment and siRNA knockdown of ATM and ATR restore significant replicative activity in HGPS cells.

    “Caffeine inhibits both ATM and ATR, and caffeine-treated HGPS cells demonstrated a significant restoration of replicative activity. Knockdown of ATM and ATR protein levels by siRNA silencing also restored significant replicative activity [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Ig-fold domain of all lamin proteins binds directly to PCNA, and excess amounts of the Ig-fold domain sequester PCNA and inhibit DNA replication.

    “Shumaker et al. also observed that the Ig-fold domain of all lamin proteins bound directly to PCNA and that excess amounts of the Ig-fold domain sequestered the PCNA and inhibited DNA replication [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Goldman, 2008, The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication, J Cell Biol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged HGPS and RD cells contain higher levels of γ-H2AX than normal BJ fibroblasts, indicating more frequent DNA DSBs.

    “They found that aged HGPS and RD cells contained higher levels of γ-H2AX than did normal BJ fibroblasts indicating more frequent DNA DSBs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Zou, 2006, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Prenyl groups are derived from the cholesterol biosynthetic pathway; statins and amino-bisphosphonates are common drugs for treatment of hypercholesterolemia.

    “The prenyl groups are derived from the cholesterol biosynthetic pathway; statins and amino-bisphosphonates are common drugs for treatment of hypercholesterolemia [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Levy, 2006, Molecular bases of progeroid syndromes, Hum Mol Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These proteins were prenylated instead by geranylgeranyl addition and some laminopathy conditions persisted.

    “Consistently these proteins were prenylated instead by geranylgeranyl addition and some of the laminopathy conditions persisted [67,68].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Gruenbaum, 2008, Rejuvenating premature aging, Nat Med

      Not checked in the free run.

    • cites [68] Lopez-Otin, 2008, Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging, Nat Med

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If progeroid proteins generate a redistribution of PCNA and/or RFC, they would cause replication fork stalling followed by DNA DSB formation.

    “If these progeroid proteins generate a redistribution of PCNA and/or RFC, they also would cause replication fork stalling followed by DNA DSB formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FTI treatment reduced farnesylated forms of progerin and FC-prelamin A and corrected nuclear dysmorphology.

    “FTI treatment did reduce farnesylated forms of progerin and FC-prelamin A and correct the nuclear dysmorphology [65,66].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Glover, 2005, Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition, Hum Mol Genet

      Not checked in the free run.

    • cites [66] Fong, 2006, Prelamin A farnesylation and progeroid syndromes, J Biol Chem

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Endogenously induced DNA damage in these cells is unrepairable and concurrent with aberrant nuclear morphology.

    “The endogenously induced DNA damage in these cells is unrepairable and concurrent with aberrant nuclear morphology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Like in HGPS, DSBs formed in normal human aging are unrepairable although genotoxin-induced DSBs in the same cells can be efficiently repaired.

    “Finally, like in HPGS, DSBs formed in normal human aging also are unrepairable although genotoxin-induced DSBs in the same cells can be efficiently repaired [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Barrett, 2004, Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Unexpected translocation of XPA to DSB sites in progeroid cells may trap this NER protein at collapsed replication forks, which subsequently may silence NER activity for repair of bulky DNA adducts such as UV photoproducts.

    “In addition, the unexpected translocation of XPA to the DSB sites in progeroid cells may trap this NER protein at the collapsed replication forks, which subsequently may silence NER activity for repair of bulky DNA adducts such as the photoproducts induced by UV irradiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In late-passage HGPS cells, there is an increase in XPA foci colocalizing with γ-H2AX and in DNA DSBs.

    “when there is an increase in XPA foci colocalizing with γ-H2AX and in DNA DSBs [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The level of γ-H2AX increases with an individual's age in tissue samples and with time in culture for primary cell explants, concomitant with a parallel increase in laminopathy-induced DNA damage and pathological changes in nuclear morphology and chromatin structures.

    “For instance, the level of γ-H2AX increases with an individual's age in tissue samples and with time in culture for primary cell explants [21,37,39], which is concomitant with a parallel increase in laminopathy-induced DNA damage and the pathological changes in nuclear morphology and chromatin structures.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Misteli, 2006, Lamin A-dependent nuclear defects in human aging, Science

      Not checked in the free run.

    • cites [37] Bonner, 2008, Delayed kinetics of DNA double-strand break processing in normal and pathological aging, Aging Cell source

      Not checked in the free run.

    • cites [39] Iliakis, 2008, {gamma}-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin, Nucl Acids Res

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Subsequent possible binding of XPA to the naked replication forks with DSBs blocks access of DSB repair proteins to the damage sites.

    “The subsequent possible binding of XPA to the “naked” replication forks with DNA double-strand breaks (DSBs) blocks the access of DSB repair proteins to the damage sites.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    DNA double-strand break repair activity is impaired in HGPS and RD cells.

    “A proposed model showing that DNA double-strand break repair activity is impaired in HGPS and RD cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FTI treatment of progeroid cells did not reduce the frequency of DNA DSBs nor the levels of γ-H2AX protein and its nuclear foci.

    “However, FTI treatment of progeroid cells did not reduce the frequency of DNA DSBs nor the levels γ-H2AX protein and its nuclei foci [12,19,52].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Zhou, 2005, Genomic instability in laminopathy-based premature aging, Nat Med

      Not checked in the free run.

    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

    • cites [52] Liu, 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The XPA action not only blocks access of DSBs to DSB repair factors but also abolishes NER to which XPA belongs.

    “The action not only blocks the access of DSBs to DSB repair factors but also abolishes NER to which XPA belongs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cells from healthy individuals express low levels of progerin from sporadic use of the cryptic splice site, resulting in similar phenotypes.

    “Cells from healthy individuals also express low levels of progerin from sporadic use of the cryptic splice site [21], resulting in similar phenotypes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Misteli, 2006, Lamin A-dependent nuclear defects in human aging, Science

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    During this process, the replication fork and its damage intermediates, now PCNA- and RFC-deficient, may become accessible for XPA binding.

    “During this process, the replication fork and its damage intermediates, now PCNA- and RFC-deficient, may become accessible for XPA binding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The amount of progerin increases with age in progeroid cells, as does the number of nuclear γ-H2AX foci and measurable DSBs as well as XPA foci.

    “Thus, the amount of progerin increases with age in progeroid cells, as does the number of nuclear γ-H2AX foci and measurable DSBs as well as XPA foci [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Zou, 2008, Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A major phenotype-inducing element of progerin and FC-prelamin A is the farnesyl moiety.

    “since it is believed that a major phenotype-inducing element of progerin and FC-prelamin A is the farnesyl moiety [14,29].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lévy, 2008, HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches, Mech Ageing Dev

      Not checked in the free run.

    • cites [29] Levy, 2006, Molecular bases of progeroid syndromes, Hum Mol Genet source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    Cellular DNA damage accumulation is a hallmark step leading to premature aging and the aging phenotypes featured with genome instability.

    “It is generally believed that cellular DNA damage accumulation is a hallmark step leading to premature aging and the aging phenotypes featured with genome instability.”
1 of 1

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Authors
Musich, P. R., & Zou, Y.
Affiliations
East Tennessee State University (US)
Corresponding author
Zou, Yue
ORCID
Musich, Phillip R.
Venue
Aging
Publisher
Impact Journals, LLC
Published
2009-01-16
Volume
1
Issue
1
Pages
28-37
ISSN
1945-4589 (ISSN-L)
DOI
10.18632/aging.100012
PMC
PMC2765059
OpenAlex
W1602375218
Cited by
117
References
71
Citations by year
2026: 1 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 1 · 2020: 5 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 8 · 2015: 10 · 2014: 6 · 2013: 8 · 2012: 10
FWCI
0.77
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by)
Funders
  • National Institute on Aging (AG031503, R03AG031503)
  • National Cancer Institute (R56CA086927, R01CA086927, CA-86927)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords
Hutchinson-Gilford progeria syndrome, restrictive dermopathy, genomic instability, DNA damage response, lamin A, progerin, ZMPSTE24, XPA, nucleotide excision repair, DNA double-strand breaks, replication fork stalling, ATM, ATR, premature aging, UV sensitivity
MeSH terms
Animals, DNA Repair, Humans, Nuclear Proteins, Progeria, Protein Precursors, Lamin Type A, Genomic Instability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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