DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A
Open accessAbstract
The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturation pathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated because of the compromise in genomic integrity. Inactivation of checkpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in these patient cells can partially overcome their early replication arrest. Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei. This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question the possibility of treatment of HGPS with FTIs alone.
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Written from the paper’s full text.
TL;DR
In HGPS and RD fibroblasts, accumulation of farnesylated prelamin A/progerin is associated with persistent DNA damage checkpoint activation, and inactivating ATM/ATR partially restores DNA synthesis. FTI treatment corrects aberrant nuclear shape but does not reduce DNA double-strand breaks or checkpoint signaling, suggesting these are independent phenotypes.
Key findings
- HGPS and RD cells showed persistent DNA damage checkpoint activation: ATM nuclear foci, ATR nuclear translocation/foci, and phosphorylation of H2AX, Chk1 (Ser-345), Chk2 (Thr-68), and p53 (Ser-15).
- DNA synthesis in HGPS and RD cells at passage 11 was more than 2-fold slower than in BJ cells; replicative capacity was lost at passage 15 for RD cells and passage 21 for HGPS cells.
- Knockdown of ATM and ATR by siRNA, or treatment with 5 mM caffeine, significantly increased DNA synthesis in HGPS cells but had no obvious effect on control BJ cells.
- FTI L-744832 reduced misshapen nuclei from 47% to 11% in RD cells (P<0.005) and from 33% to 6% in HGPS cells (P<0.001), but did not substantially reduce γ-H2AX, comet-assay DNA damage, or Chk1/Chk2 phosphorylation. Expression of farnesylation-incompetent LAΔ50-SIIM and LAΔ50 induced similar γ-H2AX accumulation in HeLa cells.
Methods
- Cell-based study using HGPS fibroblasts (Coriell no. AG11513A), human RD fibroblasts, BJ fibroblasts, and HeLa cells; treatments included 5 μM FTI L-744832 daily for 72 hours and 5 mM caffeine.
- DNA synthesis measured by [methyl-3H]thymidine incorporation; checkpoint activation assessed by immunofluorescence microscopy and Western blotting for ATM, ATR, γ-H2AX, Chk1, Chk2, and p53 phosphorylation.
- DNA damage measured by neutral comet assay; siRNA knockdown of ATR and ATM, and transfection of pEGFP-LAΔ50, pEGFP-LAΔ50-SIIM, or control plasmids were used to test effects of progerin and farnesylation status.
Limitations
- The paper states that only partial restoration of S-phase progression was observed after ATM/ATR inactivation, likely because DNA damage responses were incompletely repressed and residual kinase activity may suffice to enforce a checkpoint.
- The paper notes a discrepancy with another study on ATR localization, attributing it to ectopic FLAG-ATR expression versus endogenous ATR staining in normal cells.
- Evident from the text: findings are limited to cultured patient fibroblasts and HeLa overexpression models, with no in vivo data; FTI may not completely abolish progerin farnesylation, although the authors also used a prenylation-incompetent LAΔ50-SIIM construct to address this.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 18 cited sources checked · 0 supported · 0 flagged
- Findingown data§ Discussion
Activation of ATR and ATM in patient cells as evidenced by immunofluorescence was confirmed by phosphorylation of downstream substrates Chk1, Chk2, and p53.
“In the present study, activation of ATR and ATM in the patient cells as evidenced by immunofluorescence determination was confirmed by the phosphorylation of their downstream substrates Chk1, Chk2, and p53 as analyzed by Western blotting.”
Quote in the paperSubstantial claim - Findingown data§ Results
Chk1 and Chk2 phosphorylation was equally efficient in HGPS cells with or without FTI treatment.
“Importantly, the phosphorylation was equally efficient in the cells with or without FTI treatment.”
Quote in the paperSubstantial claim - Findingown data§ Results
No substantial reduction of DNA double-strand breaks was detected in HGPS and RD cells after FTI treatment, as evidenced by γ-H2AX.
“By contrast, however, no substantial reduction of DSBs was detected in HGPS and RD cells after FTI treatment, as evidenced by the amount of γ-H2AX analyzed by Western blotting (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data§ Results
ATR was activated in HGPS and RD cells, as indicated by its nuclear distribution.
“The nuclear distribution of ATR in RD and HGPS cells suggests its activation in these cells, which is confirmed by the phosphorylation of its primary substrate Chk1 (see below).”
Quote in the paperSubstantial claim - Findingown data§ Summary
FTI treatment did not reduce DNA damage checkpoint signaling in HGPS and RD patient cells.
“Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei.”
- Also stated in: § Results · plain
“Importantly, the phosphorylation was equally efficient in the cells with or without FTI treatment.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data§ Summary
Inactivation of checkpoint kinases ATM and ATR in HGPS and RD patient cells can partially overcome their early replication arrest.
“Inactivation of checkpoint kinases Ataxia-Telangiectasia Mutated (ATM) and ATR (ATM and RAD3-Related) in these patient cells can partially overcome their early replication arrest.”
Quote in the paperSubstantial claim - Findingown data§ Summary
FTI treatment significantly reversed the aberrant shape of nuclei in HGPS and RD patient cells.
“Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei.”
- Also stated in: § Results · plain
“As shown in Fig. 5A, treatment of HGPS and RD fibroblasts of passage 15 with L-744832, a potent FTI (Capell et al., 2005), significantly reduced the percentage of cells with misshapen nuclei (from 47% to 11% for RD cells, P < 0.005; from 33% to 6% for HGPS cells, P < 0.001).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data§ Results
Comet assays showed no substantial difference in the amount of DNA damage in HGPS cells with and without FTI treatment.
“As shown in Fig. 5C, there was no substantial difference in the amount of DNA damage generated in the cells with and without FTI treatments.”
Quote in the paperSubstantial claim - Findingown data§ Results
Treatment with caffeine similarly increased DNA synthesis in HGPS cells.
“Similar data were produced by treating the cells with caffeine (Fig. 4B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Expression of LAΔ50 and prenylation-incompetent LAΔ50-SSIM in HeLa cells induced similar levels of γ-H2AX accumulation.
“As shown in Fig. 5E, the expression of LAΔ50 and prenylation incompetent LAΔ50-SSIM in HeLa cells induced similar levels of γ-H2AX accumulation, indicating that farnesylation had no substantial effect on the cellular DNA damage accumulation induced by progerin.”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
Inactivation of ATM and ATR in HGPS cells partially restored cell-cycle progression into S phase.
“Interestingly, inactivation of ATM and ATR in HGPS cells partially restored cell-cycle progression into S phase.”
Quote in the paperSubstantial claim - Findingown data§ Results
DNA synthesis in HGPS and RD cells of passage 11 occurred at rates more than 2-fold slower than in BJ cells.
“As shown in Fig. 1, DNA synthesis in the HGPS and RD cells of passage 11 occurred at rates more than 2-fold slower than that in BJ cells, a non-transformed human diploid fibroblast cell line.”
Quote in the paperSubstantial claim - Findingown data§ Summary
FTI treatment did not reduce DNA double strand breaks in HGPS and RD patient cells.
“Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei.”
- Also stated in: § Results · plain
“By contrast, however, no substantial reduction of DSBs was detected in HGPS and RD cells after FTI treatment, as evidenced by the amount of γ-H2AX analyzed by Western blotting (Fig. 5B).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data§ Results
ATM was activated in HGPS and RD cells, as indicated by nuclear focus formation.
“Interestingly, a very similar pattern of ATM nuclear focus formation was observed in HGPS and RD cells even without treatment with CPT, suggesting that ATM was activated in these cells (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data§ Results
FTI treatment significantly reduced the percentage of cells with misshapen nuclei (from 47% to 11% for RD cells, P < 0.005; from 33% to 6% for HGPS cells, P < 0.001).
“As shown in Fig. 5A, treatment of HGPS and RD fibroblasts of passage 15 with L-744832, a potent FTI (Capell et al., 2005), significantly reduced the percentage of cells with misshapen nuclei (from 47% to 11% for RD cells, P < 0.005; from 33% to 6% for HGPS cells, P < 0.001).”
Quote in the paperNot a substantial claim - Findingown data§ Summary
In HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated.
“Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated due to the compromise of genomic integrity.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Subcellular distribution of checkpoint kinases ATM and ATR may be used as an indicator for their activation in vivo.
“We also demonstrated that the subcellular distribution of checkpoint kinases ATM and ATR may be used as an indicator for their activation in vivo.”
Quote in the paperSubstantial claim - Interpretationown data§ Summary
DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in HGPS and RD.
“This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes.”
- Also stated in: § Discussion · hedged
“This suggests that DNA damage accumulation and misshapen nuclei are probably two unrelated phenotypes caused by prelamin A accumulation in HGPS and RD.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Premisecitation§ Introduction
The point mutation (1824C → T) in LMNA results in defective maturation of lamin A from prelamin A by causing deletion of 50 amino acids near the C terminus of prelamin A.
“The point mutation (1824C → T) of LMNA results in defective maturation of lamin A from its precursor prelamin A by causing a deletion of 50 amino acids near the C terminus of prelamin A, which contains an endoprotease (Zmpste 24) cleavage site required for the proteolytic maturation of lamin A (Eriksson et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Eriksson et al., 2003
Not checked in the free run.
- Interpretationown data§ Results
Nuclear translocation of checkpoint kinases in patient cells arises from expression of prelamin A/progerin.
“This indicated that the nuclear translocation of checkpoint kinases was indeed induced by the presence of progerin.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
FTI treatment could correct the nuclear morphology defects of progeroid cells.
“Recent studies showed that FTI treatment could correct the nuclear morphology defects of progeroid cells (Capell et al., 2005; Glynn and Glover, 2005; Mallampalli et al., 2005; Toth et al., 2005).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Capell et al., 2005
Not checked in the free run.
- cites Glynn and Glover, 2005
Not checked in the free run.
- cites Mallampalli et al., 2005
Not checked in the free run.
- Premisecitation§ Results
FTI treatment ameliorates disease phenotypes in Zmpste24-deficient mice.
“FTI treatment also ameliorates disease phenotypes in Zmpste24-deficient mice (Fong et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fong et al., 2006
Not checked in the free run.
- Interpretationreasoning§ Discussion
This senescence can be suppressed by inactivating DNA damage response pathways in HGPS cells.
“Importantly, this senescence can be suppressed by inactivating DNA damage response pathways in HGPS cells.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Varela et al. showed that p53 knockout completely recovered the proliferative capacity of Zmpste24−/− mouse cells.
“Varela et al. showed that p53 knockout completely recovered the proliferative capacity of Zmpste24−/− mouse cells (Varela et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Varela et al., 2005
Not checked in the free run.
- Premisecitation§ Introduction
These mutations are predicted to result in accumulation of farnesylated and carboxymethylated prelamin A.
“Based on our prior elucidation of the prelamin A processing pathway (Sinensky et al., 1994b), these mutations are predicted to result in accumulation of farnesylated and carboxymethylated prelamin A.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sinensky et al., 1994b
Not checked in the free run.
- Premisereasoning§ Introduction
Loss of Zmpste24 activity arrests processing of prelamin A at a stage similar to HGPS.
“Loss of Zmpste 24 activity arrests the processing of prelamin A at a stage similar to HGPS, although a unique truncated prelamin A (progerin) is accumulated in HGPS cells.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Summary
The results call into question the possibility of treatment of HGPS with FTIs alone.
“Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question on the possibility of treatment of HGPS with FTIs alone.”
Quote in the paperSubstantial claim - Premisecitation§ Summary
HGPS and RD arise from accumulation of farnesylated prelamin A due to defects in the lamin A maturation pathway.
“The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A due to defects in the lamin A maturation pathway.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites De Sandre-Giovannoli et al., 2003
Not checked in the free run.
- cites Eriksson et al., 2003
Not checked in the free run.
- cites Navarro et al., 2005
Not checked in the free run.
- Interpretationown data§ Summary
The persistent activation of DNA damage checkpoints in HGPS and RD fibroblasts is due to compromised genomic integrity.
“Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated due to the compromise of genomic integrity.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Farnesylation had no substantial effect on the cellular DNA damage accumulation induced by progerin.
“indicating that farnesylation had no substantial effect on the cellular DNA damage accumulation induced by progerin.”
Quote in the paperSubstantial claim - Premisecitation§ Summary
DNA damage accumulation is an important contributor to the symptoms of HGPS.
“Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question on the possibility of treatment of HGPS with FTIs alone.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Misteli and Scaffidi, 2005
Not checked in the free run.
- May combine two claims. 10
- Classified as probably not a substantial claim. 3
May combine two claims.
Findingown data§ ResultsReplicative capacity was lost at passage 15 for RD cells and at passage 21 for HGPS cells.
“Moreover, replicative capacity was lost at passage 15 for RD cells and at passage 21 for HGPS cells (Fig. 1) in contrast to the more typical replicative behavior of BJ cells which exhibit many more passages before undergoing replicative senescence (Steinert et al., 2000).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsKnockdown of ATM and ATR by siRNA significantly increased DNA synthesis in HGPS cells, while having no obvious effect on control BJ cells.
“As shown in Fig. 4B, the knockdown significantly increased DNA synthesis in HGPS cells, while having no obvious effect on that of the control BJ cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone given§ DiscussionInactive ATM is homogenously distributed in the nucleus, while nuclear focus formation of ATM indicates its activation.
“Inactive ATM is homogenously distributed in the nucleus, while nuclear focus formation of ATM indicates its activation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsPhosphorylation of Chk1 (Ser-345), Chk2 (Thr-68), and p53 (Ser-15) were all readily detected in HGPS and RD cells, confirming activation and signaling of checkpoint pathways.
“As shown in Fig. 3, besides phosphorylation of H2AX, phosphorylation of Chk1 (Ser-345), Chk2 (Thr-68), and p53 (Ser-15) were all readily detected in HGPS and RD cells, confirming the activation and signaling of checkpoint pathways in these cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DiscussionDNA damage accumulation and misshapen nuclei are probably two unrelated phenotypes caused by prelamin A accumulation in HGPS and RD.
“This suggests that DNA damage accumulation and misshapen nuclei are probably two unrelated phenotypes caused by prelamin A accumulation in HGPS and RD.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ DiscussionA form of prelamin A (progerin) activated DNA damage responses, leading to replicative senescence.
“This confirms that a form of prelamin A (progerin) activated DNA damage responses, leading to replicative senescence.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationcitation§ DiscussionIndependent pathological pathways exist and cooperate with each other in the generation of progeroid phenotypes.
“suggesting that independent pathological pathways exist and cooperate with each other in the generation of progeroid phenotypes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionAberrant nuclear morphology is the most obvious phenotype caused by prelamin A accumulation in HGPS and RD fibroblasts.
“Aberrant nuclear morphology is the most obvious phenotype caused by prelamin A accumulation in HGPS and RD fibroblasts (Goldman et al., 2004; Toth et al., 2005).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Goldman et al., 2004
Not checked in the free run.
- cites Toth et al., 2005
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionZmpste24 mutation leads to restrictive dermopathy (RD).
“Zmpste 24 mutation leads to another progeroid disorder, restrictive dermopathy (RD), which is neonatally lethal (Navarro et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Navarro et al., 2005
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ IntroductionHGPS and RD have been suggested to be manifestations of the same cellular problem to different degrees.
“These two diseases have been suggested to be manifestations of the same cellular problem to different degrees (Misteli and Scaffidi, 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Misteli and Scaffidi, 2005
Not checked in the free run.
May combine two claims.
Premisecitation§ DiscussionIn unstressed cells, ATR is mainly localized in cytosol, but translocates into the nucleus upon DNA damaging stress such as UV irradiation.
“In unstressed cells, ATR is mainly localized in cytosol, but translocates into the nucleus upon DNA damaging stress such as UV irradiation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Abraham, 2001
Not checked in the free run.
May combine two claims.
Premisecitation§ Discussionp53 knockout can restore proliferative capacity of Zmpste24−/− mouse cells, but only partially reverse other disease phenotypes.
“Consistent with this notion, p53 knockout can restore proliferative capacity of Zmpste24−/− mouse cells, but only partially reverse other disease phenotypes (Varela et al., 2005), suggesting that independent pathological pathways exist and cooperate with each other in the generation of progeroid phenotypes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Varela et al., 2005
Not checked in the free run.
May combine two claims.
Interpretationcitation§ DiscussionOnly partial restoration of S-phase progression is likely due to incomplete repression of DNA damage responses, as even residual kinase activity could be sufficient to enforce a DNA damage checkpoint.
“That only partial restoration of S-phase progression is observed is likely due to the incomplete repression of the DNA damage responses as even a residual kinase activity could be sufficient to enforce a DNA damage checkpoint (Cortez et al., 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cortez et al., 2001
Not checked in the free run.
The paper relies on this without support.
The mechanism by which accumulation of farnesylated prelamin A leads to accelerated aging phenotypes is not understood.
“The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood.”
The paper relies on this without support.
There is no evidence for mutations in DNA repair genes in HGPS and RD cells.
“As there is no evidence for any mutations in DNA repair genes in HGPS and RD cells, we, and others, hypothesize that prelamin A accumulation affects DNA repair in these syndromes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HGPS cells with progerin accumulation have a reduced replicative lifespan and a deficiency in repairing endogenous laminopathy-induced DNA double-strand breaks, which increase with age.
“HGPS cells with progerin accumulation exhibit a reduced replicative lifespan plus a deficiency in the repair of endogenous, laminopathy-induced DNA DSBs, which increase with age 113, 114.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [113]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Prenylation-incompetent construct has two names
MinorThe same prenylation-incompetent LAΔ50 construct is called SIIM in the Results but SSIM in the Methods, leaving its designation inconsistent.
“pEGFP-LAΔ50-SIIM is a construct for expression of the LAΔ50 with a mutation at its farnesylation site”
“pEGFP-LAΔ50-SSIM (both were gifts from Dr. Francis Collins, NIH)”
Comet assay is called neutral despite alkaline DNA unwinding
MinorThe method is described as a neutral comet assay, but its stated procedure exposes the DNA to pH > 13 for 30 minutes before electrophoresis.
“The neutral comet assay was performed to assess DNA strand breaks in cells.”
“The slides were then placed in the alkaline buffer (0.3 M NaOH, 1 mM EDTA, pH > 13) for 30 minutes for DNA unwinding.”
The citation lists haven’t been fetched yet
References 36 · Cited by 228
- Authors
- Liu, Y., Rusinol, A., Sinensky, M., Wang, Y., & Zou, Y.
- Affiliations
- East Tennessee State University (US)
- Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2006-11-15
- Volume
- 119
- Issue
- 22
- Pages
- 4644-4649
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC3105909
- OpenAlex
- W2143571321
- Semantic Scholar
- db8977211d7b2bc529bc67b3a3aaf3526aad7aa5
- Cited by
- 228
- References
- 36
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 14 · 2017: 12 · 2016: 12 · 2015: 18 · 2014: 11 · 2013: 14 · 2012: 13
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- San Jose State University Scholar Works (San Jose State University) (submittedVersion)
- Funders
- 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 › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- Hutchinson-Gilford progeria syndrome, restrictive dermopathy, progeroid syndromes, prelamin A, farnesyltransferase inhibitors, DNA damage response, ATM, ATR, DNA double-strand breaks, accelerated aging, nuclear morphology, fibroblasts, replication arrest
- MeSH terms
- Cell Nucleus, DNA Replication, DNA-Binding Proteins, Enzyme Inhibitors, Fibroblasts, Humans, Nuclear Proteins, Progeria, Protein Precursors, Skin Abnormalities, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Lamin Type A, Farnesyltranstransferase, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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