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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    • "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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    ASN Neuro 06/2015; 7(3). DOI:10.1177/1759091415593066 · 4.02 Impact Factor
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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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    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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