Transcriptional regulation of cellular senescence

Lanigan, Fiona; Geraghty, James; Bracken, Adrian P.

doi:10.1038/onc.2011.34

Cited by 85 publications

(73 citation statements)

References 145 publications

(167 reference statements)

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“…37 γ-H2AX foci were observed in 10% to 12% of control and WT-prelamin-A overexpressing cells, but in 39% of cells overexpressing p.R482W-prelamin-A ( Figure 3C; Figure Figure 3D), which are cell cycle arrest proteins activated during DNA DSBs response. 38 Finally, senescence-activated β-galactosidase activity was enhanced in p.R482W but not in WT-prelamin-A expressing endothelial cells ( Figure 3E). …”

Section: Pr482w But Not Wt-prelamin-a Expression Led To Increased Oxmentioning

confidence: 92%

“…Failure of DNA repair results in increased expression of p53 and of cell cycle arrest checkpoint kinases. 38 DNA damages and increased H 2 AX phosphorylation were observed in atherosclerotic plaques. 46 We show here, for the first time, that overexpression of p.R482W-prelamin-A led to an increased number of DNA DSBs, revealed by γH 2 AX phosphorylation, in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

Bidault

Garcia

Vantyghem

et al. 2013

ATVB

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A -type lamins are intermediate filaments and major components of the nuclear lamina, a filamentous network underlying the inner nuclear membrane that provides structural and mechanical stability for the nucleus in nearly all differentiated cells. A-type lamins interact with heterochromatin and transcriptional regulators, highlighting their important role in chromatin organization, gene expression, and DNA repair.1 The 2 main A-type lamin isoforms, lamin-A and lamin-C, arise from alternative splicing of the LMNA gene. The precursor of lamin-A, prelamin-A, undergoes a complex post-translational maturation comprising a step of C-terminal farnesylation followed by carboxymethylation and a proteolytic cleavage by the metalloprotease ZMPSTE24, resulting in the carboxymethylated C-terminal removal of the protein, including its farnesyl group, and in the release of mature lamin-A. 1LMNA mutations cause inherited diseases commonly named laminopathies, including muscular dystrophies, cardiomyopathies, progeroid phenotypes, and lipodystrophic syndromes.2 Among them, the Dunnigan-type familial partial lipodystrophy (FPLD2; OMIM #151660) is mainly attributable to LMNA p.R482 heterozygous substitutions. 3,4 This syndrome is characterized by a gradual atrophy of subcutaneous adipose tissue in the extremities, gluteal, and truncal areas © 2013 American Heart Association, Inc. heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patients' fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction. Conclusions-LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients' early atherosclerosis. (Arterioscler Thromb Vasc Biol. 2013;33:2162-2171.)

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Section: Pr482w But Not Wt-prelamin-a Expression Led To Increased Oxmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

Bidault

Garcia

Vantyghem

et al. 2013

ATVB

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“…HIRA-mediated deposition of H3.3 regulates chromatin dynamics in senescent cells and is, in part, responsible for the formation of SAHF (29,33,48). SAHF, in turn, repress the transcription of proliferation-related genes, including Cyclin A, minichromosome maintenance complex 6 (MCM6), and PCNA, thereby maintaining permanent cell-cycle arrest in senescent cells (32,55). In addition to SAHF formation, the cellular transition from proliferation to senescence is marked by increased expression of the cell cycle inhibitor p16 INK4A and enhanced staining with SA β-gal.…”

Section: Resultsmentioning

confidence: 99%

O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

Lee

Zhang

2016

Proc. Natl. Acad. Sci. U.S.A.

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The histone chaperone HIRA complex, consisting of histone cell cycle regulator (HIRA), Ubinuclein1 (UBN1), and calcineurin binding protein 1 (CABIN1), deposits histone variant H3.3 to genic regions and regulates gene expression in various cellular processes, including cellular senescence. How HIRA-mediated nucleosome assembly of H3.3-H4 is regulated remains not well understood. Here, we show that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), an enzyme that catalyzes O-GlcNAcylation of serine or threonine residues, interacts with UBN1, modifies HIRA, and promotes nucleosome assembly of H3.3. Depletion of OGT or expression of the HIRA S231A O-GlcNAcylation-deficient mutant compromises formation of the HIRA-H3.3 complex and H3.3 nucleosome assembly. Importantly, OGT depletion or expression of the HIRA S231A mutant delays premature cellular senescence in primary human fibroblasts, whereas overexpression of OGT accelerates senescence. Taken together, these results support a model in which OGT modifies HIRA to regulate HIRA-H3.3 complex formation and H3.3 nucleosome assembly and reveal the mechanism by which OGT functions in cellular senescence.

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“…Thus, in spite of any DNA damage that may exist in a long-lived cell, if this cell is senescent it will not undergo clonal expansion to generate daughter cells with altered DNA. A number of molecular mechanisms control cellular senesce, and the E2F/pRb pathway is a key component (Lanigan et al, 2011). Under normal circumstances, the frequency of DNA mutations increases with age.…”

Section: Role Of E2f-1 In Senescence-associated Dna Damagementioning

confidence: 99%

“…Senescence is defined as irreversible cell cycle arrest, which occurs both in cultured cells and in vivo (Lanigan et al, 2011). Senescence has been recognized as a key mechanism that acts as a barrier to tumour formation and progression.…”

Section: Role Of E2f-1 In Senescence-associated Dna Damagementioning

confidence: 99%

Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning DNA Repair, Cell Cycle Progression and Survival in Development & Disease

Dagnino¹,

Singh²,

Judah³

2011

DNA Repair

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Transcriptional regulation of cellular senescence

Cited by 85 publications

References 145 publications

Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

Post-Transcriptional Regulation of E2F Transcription Factors: Fine-Tuning DNA Repair, Cell Cycle Progression and Survival in Development & Disease

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