Heterochromatin and its Relationship to Cell Senescence and Cancer Therapy

Zhang, Rugang; Adams, Peter D.

doi:10.4161/cc.6.7.4079

Cited by 93 publications

(70 citation statements)

References 86 publications

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“…We also tested for phosphorylation of heterochromatin protein 1-γ (HP1-γ), a nonhistone protein involved in gene silencing and chromatin organization that is phosphorylated in response to DNA damage to initiate the DDR (15). In cells entering senescence, phosphorylation of HP1-γ is thought to be required for its efficient incorporation into specialized domains of facultative heterochromatin called senescence associated heterochromatin foci (16).…”

Section: Resultsmentioning

confidence: 99%

Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

Rajagopalan

Long

2012

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

140

144

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Natural killer (NK) cells, which have an essential role in immune defense, also contribute to reproductive success. NK cells are abundant at the maternal-fetal interface, where soluble HLA-G is produced by fetal trophoblast cells during early pregnancy. Soluble HLA-G induces a proinflammatory response in primary, resting NK cells on endocytosis into early endosomes where its receptor, CD158d, resides. CD158d initiates signaling through DNA-PKcs, Akt, and NF-κB for a proinflammatory and proangiogenic response. The physiological relevance of this endosomal signaling pathway, and how activation of CD158d through soluble ligands regulates NK cell fate and function is unknown. We show here that CD158d agonists trigger a DNA damage response signaling pathway involving cyclindependent kinase inhibitor p21 expression and heterochromatin protein HP1-γ phosphorylation. Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence, and a transcriptional signature of a senescence-associated secretory phenotype (SASP). SASP is a program that can be induced by oncogenes or DNA damage, and promotes growth arrest and tissue repair. The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. Retrospective analysis of the decidual NK cell transcriptome revealed a strong senescence signature. We propose that a positive function of senescence in healthy tissue is to favor reproduction through the sustained activation of NK cells to remodel maternal vasculature in early pregnancy.KIR2DL4 | microarray

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Section: Resultsmentioning

confidence: 99%

Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

Rajagopalan

Long

2012

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

140

144

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“…In particular, analysis of DNA methylation patterns suggests that mammalian aging is associated with an overall decrease in heterochromatin, but an increase at specific sites in the genome. Conceivably, there is a "redistribution" of transcriptionsilencing heterochromatin from repetitive DNA, that is normally packaged into constitutive heterochromatin, to regions of the genome that are normally transcribed [57][58][59].…”

Section: Aging Is Associated With Epigenetic Changes From Yeast To Hmentioning

confidence: 99%

“…Remarkably, although SAHF appear to result from the condensation of almost entire chromosomes, DNA sequences that are typically contained in constitutive heterochromatin, such as pericentromeres and telomeres, actually appear to be excluded from the bulk of the condensed chromosome [57,90,91,93]. This suggests that these normally constitutively heterochromatic regions are perhaps deheterochromatinized in senescent cells.…”

Section: Cellular Senescence Is Associated With Redistribution Of Hetmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

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137

102

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Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

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“…[12][13][14] Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senescence regulator, which is typically activated during senescence and enforces the expression of other senescence-inducing proteins. [16][17][18] RB protein has a specific E2F-binding domain to suppress E2F activity.…”

mentioning

confidence: 99%

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...

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Heterochromatin and its Relationship to Cell Senescence and Cancer Therapy

Cited by 93 publications

References 86 publications

Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

Aging by epigenetics—A consequence of chromatin damage?

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

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