Methylation-Acetylation Interplay Activates p53 in Response to DNA Damage

Ivanov, Gleb; Иванова, Т. А.; Kurash, Julia K.; Ivanov, Alexey V.; Chuikov, Sergey; Gizatullin, Farid; Herrera-Medina, Enrique M.; Rauscher, Frank J.; Reinberg, Danny; Barlev, Nickolai A.

doi:10.1128/mcb.00460-07

Cited by 186 publications

(206 citation statements)

References 60 publications

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“…Therefore, although the p53 methylation mediated by Set7/9 may contribute to the p53 transactivation potential, the interaction of SIRT1 and Set7/9 may have a more critical role in enhancing p53 activity. In addition, the interaction of SIRT1 and Set7/9 may explain why Set7/9 knockdown induces p53 deacetylation at K382 (31,32), thus providing the mechanistic basis for linking p53 methylation at K372 to p53 acetylation at K382.…”

Section: Discussionmentioning

confidence: 99%

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

Liu

Wang

Zhao

et al. 2011

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

122

113

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Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism. T he class III HDAC sirtuins, SIRT1 to SIRT7, are homologous to yeast silent information regulator 2 (Sir2) and play important biological roles during aging, metabolism, and autophagy (1, 2). Within the sirtuins, SIRT1 is the closest homolog of yeast Sir2. In contrast to class I and II HDACs, sirtuins require nicotinamide adenine dinucleotide (NAD + ) as a coenzyme to act on their target proteins (3). Numerous studies have also suggested a role for SIRT1 in the development of tumors because SIRT1 is up-regulated in various cancerous tissues and cell lines, such as leukemia and prostate cancer (4, 5). In addition, SIRT1 is overexpressed in several p53-deficient tumor cell lines, and the transient knockdown of SIRT1 leads to increased apoptosis after DNA damage or oxidative stress (6). Moreover, tumor suppressors such as p53 (7,8) and FoxO (9,10) are deacetylated by SIRT1 and, thus, inactivated in response to DNA damage, which provides further evidence that SIRT1 is an oncogenic protein.The tumor suppressor hypermethylated in cancer 1 (HIC1) has been shown to inhibit SIRT1 expression by forming a repressive complex with SIRT1 on its own promoter and sensitizing the p53 response to DNA damage (11). In addition, deleted in breast cancer 1 (DBC1) has also been reported to be a negative repressor of SIRT1 in various cell lines and leads to increased levels of p53 acetylation and up-regulation of p53 transcriptional activities (12, 13). However, active regulator of SIRT1 (AROS) interacts with SIRT1 and activates its deacetylase activity (14). In addition to protein interactions, posttranslational modifications of SIRT1 are also important for its activity. For instance, SIRT1 is phosphorylated by J...

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Section: Discussionmentioning

confidence: 99%

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

Liu

Wang

Zhao

et al. 2011

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

122

113

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“…Multiple residues of each core histone have been identified as modification sites and some of the same lysine side chains can be either methylated or acetylated in a cellular context-specific manner (22,23). For p53, K372 is methylated by the H3K4 methylase SET7/9, enhancing the subsequent acetylation of the same residue and in turn stabilizing p53 (24). In addition, the previously identified acetylated sites K314/K315 that are modified by CBP/p300 (18) were also recently identified as substrates for monomethylation catalyzed by the histone H3K4 methylase SET9 (25).…”

Section: Discussionmentioning

confidence: 99%

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Lü

Jackson²,

Wang

et al. 2009

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

260

213

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NF-κB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-κB regulatory pathway that is driven by reversible lysine methylation of the p65 subunit, carried out by a lysine methylase, the nuclear receptorbinding SET domain-containing protein 1 (NSD1), and a lysine demethylase, F-box and leucine-rich repeat protein 11 (FBXL11). Overexpression of FBXL11 inhibits NF-κB activity, and a high level of NSD1 activates NF-κB and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-κB activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-κB. Overexpression of FBXL11 slowed the growth of HT29 cancer cells, whereas shRNA-mediated knockdown had the opposite effect, and these phenotypes were dependent on K218/K221 methylation. In mouse embryo fibroblasts, the activation of most p65-dependent genes relied on K218/K221 methylation. Importantly, expression of the FBXL11 gene is driven by NF-κB, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-κB is an important element in the complex regulation of this key transcription factor. [RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52)], the p65/p50 heterodimer functions most often in the "classical" signaling pathway (1). Constitutive NF-κB activation is frequently associated with a number of pathological conditions, including inflammation and cancer, and is well known to be involved in tumor angiogenesis and invasiveness (2). Loss of the normal regulation of NF-κB is a major contributor to the deregulated growth, resistance to apoptosis, and propensity to metastasize observed in many different cancers (3). Our data, showing NF-κB activation in many cancer-derived cell lines (4, 5), further support the strong correlation between constitutive NF-κB activation and cancer. Thus, understanding the complexity of NF-κB-dependent signaling is an important aspect of dealing with these diseases.NF-κB has a variety of functions and is regulated by hundreds of different stimuli in different cell types (6). Specialized control of NF-κB activity is critical for achieving its normal transient activation in response to stress. Regardless of the stimulus, all pathways leading to NF-κB activation depend on inducing posttranslational modifications of the IκB kinase, IκB proteins, or NF-κB subunits. These regulatory modifications, including phosphorylation, ubiquitination, acetylation, sumolation, and nitrosylation, vary depending on the specific stimulus and context (7).We have developed a lentiviral validation-based insertional (VBIM) method to create mutant cell lines in which the overexpression of specific cellular proteins, driven by inserted CMV promoters, is responsible for altered phenotypes. We used this method to identify the F-box and leucine-rich repeat protein 11 (FBXL11) as a potent negative regulator of NF-κB and to show that its demethylase activity was required for this function (8). FBXL11, previous...

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“…U2OSp53 Ϫ/Ϫ (U2OS stably transfected with a pLKO-p53-shRNA-941 vector to suppress p53 expression using methods described previously (27)) were maintained in DMEM supplemented with 10% FBS, penicillin-streptomycin (50 units/ml), and puromycin (2 g/ml). U2OSp53 Ϫ/Ϫ were generously provided by Dr. Nickolai Barlev (University of Leicester, UK).…”

Section: Methodsmentioning

confidence: 99%

Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21

Masgras

Carrera

Verdier

et al. 2012

Journal of Biological Chemistry

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Background: For unknown reasons, p21 expression induces different effects in cells, including arrest, death, and growth/ prosurvival signals. Results: Cancer cell lines respond with arrest or apoptosis to p21 expression depending on mitochondria sensitivity to oxidants. Conclusion: Cell-specific sensitivity to oxidative stress determines p21-induced cell death.Significance: This provides a rationale to find therapies that up-regulate p21 in cells that are more sensitive to oxidants to favor a death response.

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Methylation-Acetylation Interplay Activates p53 in Response to DNA Damage

Cited by 186 publications

References 60 publications

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21

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