Regulation of p53 activity through lysine Methylation

Department of Biological Sciences, Columbia University, New York, New York, United States
Nature (Impact Factor: 41.46). 12/2004; 432(7015):353-60. DOI: 10.1038/nature03117
Source: PubMed


p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase.

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    • "These post-translational modifications can occur in an exclusive or combined manner, and may reinforce or diminish the potential of PGC-1a to co-activate transcription under diverse metabolic conditions (Cantó and Auwerx, 2009), resulting in defective control of multiple transcriptional networks (Lerin et al., 2006; Li et al., 2007; Teyssier et al., 2005). On the other hand, lysine methylation by the histone mono-methyltransferase SET7/9, and lysine demethylation by the Lysine Specific Demethylase 1 (LSD1), have been shown to play an important role in non-histone proteins such as p53 and DNMT1 (Chuikov et al., 2004; Estè ve et al., 2009; Nicholson and Chen, 2009; Pradhan et al., 2009; Wang et al., 2009). Chemical modification also occurs on RNA, functioning as a sensor of the metabolic status to influence gene regulatory networks at the epigenetic level (Towns and Begley, 2012). "
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    ABSTRACT: The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m5C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m5C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "cific promoters ( Sims and Reinberg , 2008 ) . Furthermore , since lysine residues that can be subjected to acetylation are also targeted by methyl - transferases , with opposing effects on p53 function , it will be of interest to analyse the methylation profile of p53 . For example , methylation at K372 can enhance p53 - dependent transcription ( Chuikov et al . , 2004 ) , whereas methylation at K370 mediates repression of transcriptional activity ( Huang et al . , 2006 ) ."
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    ABSTRACT: Histones deacetylases (HDACs), besides their function as epigenetic regulators, deacetylate and critically regulate the activity of nonhistone targets. In particular, HDACs control partially the proapoptotic activity of p53 by balancing its acetylation state. HDAC inhibitors have revealed neuroprotective properties in different models, but the exact mechanisms of action remain poorly understood. We have generated a conditional knockout mouse model targeting retinal ganglion cells (RGCs) to investigate specifically the functional role of HDAC1 and HDAC2 in an acute model of optic nerve injury. Our results demonstrate that combined HDAC1 and HDAC2 ablation promotes survival of axotomized RGCs. Based on global gene expression analyses, we identified the p53-PUMA apoptosis-inducing axis to be strongly activated in axotomized mouse RGCs. Specific HDAC1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection due to HDAC1/2 depletion. HDAC1/2 inhibition and the affected downstream signaling components emerge as specific targets for developing therapeutic strategies in neuroprotection. © The Author(s) 2015.
    Preview · Article · Jun 2015 · ASN Neuro
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    • "In contrast to myriad studies on the central DBD which are in general agreement, we still do not understand the roles and functions of the p53 CTD, whose several lysines when unmodified allow it to bind non-specifically to DNA and RNA (Laptenko and Prives, 2006). Published reports have implicated CTD involvement in regulation of DNA binding (Anderson et al., 1997; Gu and Roeder, 1997; Luo et al., 2004; McKinney et al., 2004), p53 stability (Li et al., 2002; Nakamura et al., 2000; Rodriguez et al., 2000), p53 cellular localization (Gu et al., 2001; Lohrum et al., 2001; Nie et al., 2007; Stommel et al., 1999), and co-factor recruitment (An et al., 2004; Barlev et al., 2001; Chuikov et al., 2004; Lee et al., 2000; Mujtaba et al., 2004). Unfortunately, because of its unstructured nature, nuclear magnetic resonance (NMR) and X-ray crystallography have been unable to dissect the role(s) of the CTD within the full-length p53 tetramer. "
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    ABSTRACT: DNA binding by numerous transcription factors including the p53 tumor suppressor protein constitutes a vital early step in transcriptional activation. While the role of the central core DNA binding domain (DBD) of p53 in site-specific DNA binding has been established, the contribution of the sequence-independent C-terminal domain (CTD) is still not well understood. We investigated the DNA-binding properties of a series of p53 CTD variants using a combination of in vitro biochemical analyses and in vivo binding experiments. Our results provide several unanticipated and interconnected findings. First, the CTD enables DNA binding in a sequence-dependent manner that is drastically altered by either its modification or deletion. Second, dependence on the CTD correlates with the extent to which the p53 binding site deviates from the canonical consensus sequence. Third, the CTD enables stable formation of p53-DNA complexes to divergent binding sites via DNA-induced conformational changes within the DBD itself. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Molecular Cell
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