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

ABSTRACT 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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Available from: Jon R Wilson, Sep 28, 2015
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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.
    Molecular Cell 03/2015; 57(6). DOI:10.1016/j.molcel.2015.02.015 · 14.02 Impact Factor
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    • "Single PTMs of p53 have been shown to have an impact on transcriptional and transcription-independent functions of p53 (Berger, 2010; Chuikov et al., 2004; Huang and Berger, 2008; Huang et al., 2006, 2007, 2010; Kachirskaia et al., 2008; Shi et al., 2007). However, characterization of cross-regulation or combinatorial action of multiple dynamic marks on p53 remains a daunting challenge. "
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    ABSTRACT: Individual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses; however, much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 cofactors, including 53BP1 and p300. The 1.8 Å resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The α-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and nuclear magnetic resonance analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Structure 02/2015; 23(2):322-31. DOI:10.1016/j.str.2014.12.010 · 5.62 Impact Factor
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    • "SMYD2 methylates both histones (H2B, H3 and H4) and nonhistone proteins, including the tumour suppressor proteins, p53 and Rb, and the oncogenic protein, PARP1 (Brown et al, 2006; Huang et al, 2006; Abu-Farha et al, 2008; Wu et al, 2011). Methylation of K370 of p53 impairs its ability to bind to the promoters of target genes (Chuikov et al, 2004; Huang et al, 2006). Methylation of Rb at K860 generates an epitope that is selectively recognised by the transcriptional repressor L3MBTL1, providing a mechanism for recruiting L3MBTL1 to the promoters of specific Rb/E2F target genes, thereby repressing their activities (Saddic et al, 2010). "
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    ABSTRACT: Background: SET and MYND domain-containing protein 2 (SMYD2) is a lysine methyltransferase for histone H3, p53 and Rb and inhibits their transactivation activities. In this study, we tested whether SMYD2 (1q42) acts as a cancer-promoting factor by being overexpressed in gastric cancer. Methods: We analysed 7 gastric cancer cell lines and 147 primary tumor samples of gastric cancer, which were curatively resected in our hospital. Results: SET and MYND domain-containing protein 2 was detected in these cell lines (five out of seven cell lines; 71.4%) and primary tumor samples (fifty-six out of one hundred and forty-seven cases; 38.1%). Knockdown of SMYD2 using specific small interfering RNA inhibited proliferation, migration and invasion of SMYD2-overexpressing cells in a TP53 mutation-independent manner. Overexpression of SMYD2 protein correlated with larger tumor size, more aggressive lymphatic invasion, deeper tumor invasion and higher rates of lymph node metastasis and recurrence. Patients with SMYD2-overexpressing tumours had a worse overall rate of survival than those with non-expressing tumours (P=0.0073, log-rank test) in an intensity and proportion score-dependent manner. Moreover, multivariate analysis demonstrated that SMYD2 was independently associated with worse outcome (P=0.0021, hazard ratio 4.25 (1.69-10.7)). Conclusions: These findings suggest that SMYD2 has a crucial role in tumor cell proliferation by its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in gastric cancer.
    British Journal of Cancer 10/2014; 112(2). DOI:10.1038/bjc.2014.543 · 4.84 Impact Factor
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