RNA content in the nucleolus alters p53 acetylation via MYBBP1A

Kuroda, Takeshi; Murayama, Akiko; Katagiri, Naohiro; Ohta, Yumi; Fujita, Etsuko; Masumoto, Hiroshi; Ema, Masatsugu; Takahashi, Satoru; Kimura, Kazuhiro; Yanagisawa, Junn

doi:10.1038/emboj.2011.23

Cited by 68 publications

(96 citation statements)

References 103 publications

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“…Ribonuclease A Treatment-Ribonuclease A (RNase A) 1 treatments was performed as described (15), with slight modifications. HeLa cells were grown on millicell EZ slides (Millipore, Billerica, MA) and treated with 0.2 mg/ml RNase A. Mock treatments were performed using 0.02% Triton X-100/2 mM MgCl 2 /PBS, but without RNase A.…”

Section: Methodsmentioning

confidence: 99%

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Sirtuin 7 Plays a Role in Ribosome Biogenesis and Protein Synthesis

Tsai

Greco

Cristea

2014

Molecular & Cellular Proteomics

105

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It has been shown that SIRT7 regulates rDNA transcription and that reduced SIRT7 levels inhibit tumor growth. This anti-tumor effect could be due to reduced Pol I activity and perturbed ribosome biogenesis. In this study, using pulse labeling with RNA and amino acid analogs, we found that SIRT7 knockdown efficiently suppressed both RNA and protein synthesis. Surprisingly, SIRT7 knockdown preferentially inhibited protein synthesis over rDNA transcription, whereas the levels of both were reduced to similar extents following Pol I knockdown. Using an affinity purification mass spectrometry approach and functional analyses of the resulting SIRT7 interactome, we identified and validated SIRT7 interactions with proteins involved in ribosomal biogenesis. Indeed, SIRT7 co-fractionated with monoribosomes within a sucrose gradient. Using reciprocal isolations, we determined that SIRT7 interacts specifically with mTOR and GTF3C1, a component of the Pol III transcription factor TFIIIC2 complex. Further studies found that SIRT7 knockdown triggered an increase in the levels of LC3B-II, an autophagosome marker, suggesting a link between SIRT7 and the mTOR pathway. Additionally, we provide several lines of evidence that SIRT7 plays a role in modulating Pol III function. Immunoaffinity purification of SIRT7-GFP from a nuclear fraction demonstrated specific SIRT7 interaction with five out of six components of the TFIIIC2 complex, but not with the TFIIIA or TFIIIB complex, the former of which is required for Pol III-dependent transcription of tRNA genes. ChIP assays showed SIRT7 localization to the Pol III targeting genes, and SIRT7 knockdown triggered a reduction in tRNA levels. Taken together, these data suggest that SIRT7 may regulate Pol III transcription through mTOR and the TFIIIC2 complex. We propose that SIRT7 is involved in multiple pathways involved in ribosome biogenesis, and we hypothesize that its down-regulation may contribute to an antitumor effect, partly through the inhibition of protein synthesis. Molecular &

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Section: Methodsmentioning

confidence: 99%

“…Many nucleolar proteins, such as MYBBP1A, which we have previously shown to associate with SIRT7 (8), are RNA-binding proteins (15). Therefore, we asked whether the nucleolar localization of SIRT7 and its co-localization with the Pol I complex also rely on the presence of RNA.…”

Section: Sirt7 Has An Rna-independent Nucleolar Localization and Intementioning

confidence: 99%

Sirtuin 7 Plays a Role in Ribosome Biogenesis and Protein Synthesis

Tsai

Greco

Cristea

2014

Molecular & Cellular Proteomics

105

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“…MYBBP1A, which is anchored to the nucleolus through RNA, translocates from the nucleolus to the nucleoplasm when nucleolar RNA content is reduced by inhibition of rRNA transcription. The translocated MYBBP1A acetylates and accumulates p53 by facilitating the interaction between p53 and histone acetyltransferase p300 (27). Given that nutrient shortage can reduce nucleolar RNA content by suppressing rRNA transcription, MYBBP1A may cause activation of p53 that is induced by glucose deprivation.…”

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confidence: 99%

Novel Nucleolar Pathway Connecting Intracellular Energy Status with p53 Activation

Kumazawa

Nishimura

Kuroda

et al. 2011

Journal of Biological Chemistry

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In response to a shortage of intracellular energy, mammalian cells reduce energy consumption and induce cell cycle arrest, both of which contribute to cell survival. Here we report that a novel nucleolar pathway involving the energy-dependent nucleolar silencing complex (eNoSC) and Myb-binding protein 1a (MYBBP1A) is implicated in these processes. Namely, in response to glucose starvation, eNoSC suppresses rRNA transcription, which results in a reduction in nucleolar RNA content. As a consequence, MYBBP1A, which is anchored to the nucleolus via RNA, translocates from the nucleolus to the nucleoplasm. The translocated MYBBP1A induces acetylation and accumulation of p53 by enhancing the interaction between p300 and p53, which eventually leads to the cell cycle arrest (or apoptosis). Taken together, our results indicate that the nucleolus works as a sensor that transduces the intracellular energy status into the cell cycle machinery.Intracellular energy balance is important for cell survival. In response to nutrient or environmental stresses that cause reduction in the intracellular energy level, mammalian cells sense the intrinsic energy status and attempt to restore bioenergetic homeostasis through compensatory changes in the regulation of intermediate metabolic processes. One such mechanism is the reduction of ribosome biosynthesis, a major biosynthetic and energy-consuming process in mammalian cells, whereas the other mechanism is the arrest of cell proliferation. The LKB1-AMP-activated protein kinase (AMPK) 3 pathway is reportedly involved in both regulatory processes (1-5). During energy starvation or glucose deprivation, when the cellular AMP/ATP ratio is increased, the LKB1-AMPK pathway is activated. This signaling in turn inhibits the mammalian target of rapamycin (mTOR)/p70 S6 kinase activity that is required for rapid and sustained serum-induced ribosomal biosynthesis (2). In addition to this regulation, AMPK, which is reportedly activated in response to reduced energy level, phosphorylates and activates p53, which leads to G 1 cell cycle arrest (6). Inhibition of mTOR by AMPK and G 1 cell cycle arrest by AMPK via p53 activation suppresses energy expenditure and protects cells from energy deprivation-induced apoptosis (4, 5).On the other hand, a recent study in our laboratory revealed that glucose deprivation also reduces rRNA synthesis, which leads to down-regulation of ribosome biosynthesis in HeLa cells lacking the LKB1-AMPK pathway (7). We found that a novel nucleolar protein, nucleomethylin (NML), forms an energy-dependent nucleolar silencing complex (eNoSC) with SIRT1 and SUV39H1 and functions in this process. Our results suggest that an energy-dependent change in the NAD ϩ /NADH ratio regulates eNoSC, allowing the complex to couple the changing energy status with the level of rRNA transcription by regulating the epigenetic status of rRNA clusters. eNoSC promotes the restoration of energy balance and protects cells from energy deprivation-induced apoptosis (7).With regard to p53 activation, several...

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“…8,25 Next, post-translational modification factors modify p53 to maintain its stability and activity. 8 The following factors have been identified: p300/ CBP 26 acetylates p53 to increase p53 stability and activity; SOX4 is an important p53 regulator in the cellular response to DNA damage; 6 MYBBP1A enhances the interaction between p53 and p300, which promotes p53 acetylation in response to ribosomal stress; 27 and RPL11 is required for p53 acetylation and p300 recruitment to the promoter regions of the p53 target gene in response to ribosomal stress. 28 In this study, we found that NLK binds to not only p53 but also to MDM2, and NLK stabilizes p53 by abrogating the p53-MDM2 interaction.…”

Section: Discussionmentioning

confidence: 99%

Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage

et al. 2014

Cell Death Differ

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The DNA damage response (DDR) acts as a protective mechanism for maintaining cell homeostasis. Nemo-like kinase (NLK) is a serine/threonine-protein kinase that has an important role in many pathways; however, its function in the DDR has not yet been defined. In our study, NLK-deficient HCT116 cells were found to be resistant to etoposide-induced cell death. We demonstrated that NLK is required for p53 activation in response to DNA damage. Remarkably, mechanistic studies revealed that NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. Furthermore, NLK enhances p53 activity and affects expression downstream of p53. Interestingly, these functions of NLK are not related to its kinase activity. Consistent with these results, NLK-deficient cells have a resistance effect on DNA damage. Therefore, these findings emphasize that NLK is a novel factor in DDR mechanisms.

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RNA content in the nucleolus alters p53 acetylation via MYBBP1A

Cited by 68 publications

References 103 publications

Sirtuin 7 Plays a Role in Ribosome Biogenesis and Protein Synthesis

Sirtuin 7 Plays a Role in Ribosome Biogenesis and Protein Synthesis

Novel Nucleolar Pathway Connecting Intracellular Energy Status with p53 Activation

Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage

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