Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer

Micco, Raffaella Di; Sulli, Gabriele; Dobreva, Miryana; Liontos, Michalis; Botrugno, Oronza A.; Gargiulo, Gaetano; Zuffo, Roberto Dal; Matti, Valentina; Giorgini, Dario; Montani, Erica; Mercurio, Ciro; Hahn, William C.; Gorgoulis, Vassilis G.; Minucci, Saverio; Fagagna, Fabrizio d’Adda di

doi:10.1038/ncb2170

Cited by 298 publications

(335 citation statements)

References 64 publications

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“…S7C). H3K9 methylation did not accumulate further in G0-arrested cells, suggesting that accumulation of this modification requires an S-phase arrest as previously reported (Di Micco et al 2011;Xu et al 2012). However, for several other methylation marks, including H3K27me2/3, H3K79me1/me2, and H4K20me2/me3, withdrawal from the cell cycle was indeed accompanied by a significant increase ( Fig.…”

Section: Cell Cycle Withdrawal Impacts Histone Ptm Levelsmentioning

confidence: 56%

Two distinct modes for propagation of histone PTMs across the cell cycle

et al. 2015

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Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di-and trimethylation marks are diluted twofold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.

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Section: Cell Cycle Withdrawal Impacts Histone Ptm Levelsmentioning

confidence: 56%

Two distinct modes for propagation of histone PTMs across the cell cycle

et al. 2015

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“…S6). Based on our observations, we hypothesize that the increase in heterochromatin markers observed in Prep1 knock-down cells can actually be the consequence of an oncogene-like replication stress (49).…”

Section: Discussionmentioning

confidence: 99%

Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability

Iotti

Longobardi

Masella

et al. 2011

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

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Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1 i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1 i/i MEFs, together with an increase in heterochromatin-associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogeneinduced senescence, and H-Ras V12 -dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.

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“…S7). This was not unexpected because SAHF has recently been linked to senescence that is mediated by DNA damage or p16 activation (22,23). Finally, we examined whether RAS-induced senescence was mediated through p21 by creating shp53-HMEC expressing an shRNA targeting p21.…”

Section: Resultsmentioning

confidence: 99%

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Cipriano¹,

Kan²,

Graham³

et al. 2011

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

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Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/ RB-and p53-independent OIS in response to oncogenic RAS that requires TGF-β signaling. Suppression of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor, use of a TGF-β type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-β signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-β receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. (ii) constitutive growth signaling, (iii) unlimited replication potential, and (iv) invasive potential (1). Early studies using normal mouse cells indicated that a limited set of genetic manipulations could confer neoplastic potential (2). However, normal human cells have been more difficult to transform to malignancy, indicative of their more stringent tumor-suppressive pathways. Extensive study of cultured human mammary epithelial cells (HMEC) has identified two senescence barriers. One involves the stress-associated induction of the cyclin-dependent kinase inhibitor p16 before attaining critically short telomeres. This stasis barrier can be overcome by inhibiting p16, allowing continued proliferation, which results in agonescence, a proliferative barrier mediated by telomere depletion (3). Additionally, the ability of dysregulated oncogenic signaling to induce senescence in human cells has implicated oncogene-induced senescence (OIS) as an important tumor-suppressive barrier. A number of recent studies have demonstrated the physiological relevance of OIS in human tumorigenesis and in vivo tumor mouse models (4). Additionally, the presence of senescent cells in benign but not advanced tumors argues that OIS serves as an early tumorsuppressive barrier that needs to be dismantled for full oncogenic progression (4). In human fibroblasts, OIS could be bypassed by disabling p16 or molecular components of the DNA damage response (DDR), including ATM, CHK2, or p53, before RAS, MOS, or STAT5 overexpression (5-9). However, OIS in HMEC has been shown to be independent of p53 and the p16-RB pathway after oncogenic RAF-1 expression (10). The contrasting responses between epithelial and fibroblast cells argue that the signaling networks responsible for OIS have tissue specificity. Indeed, fibrob...

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Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer

Cited by 298 publications

References 64 publications

Two distinct modes for propagation of histone PTMs across the cell cycle

Two distinct modes for propagation of histone PTMs across the cell cycle

Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

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