Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
Journal of Cellular Physiology (Impact Factor: 3.84). 11/2010; 225(2):371-84. DOI: 10.1002/jcp.22224
Source: PubMed


The ubiquitin-like molecule, SUMO-1, a small protein essential for a variety of biological processes, is covalently conjugated to many intracellular proteins, especially to regulatory components of the transcriptional machinery, such as histones and transcription factors. Sumoylation provides either a stimulatory or an inhibitory signal for proliferation and for transcription, but the molecular mechanisms by which SUMO-1 achieves such versatility of effects are incompletely defined. The tumor suppressor and transcription regulator p53 is a relevant SUMO-1 target. Particularly, the C-terminal tail of p53 undergoes both sumoylation and acetylation. While the effects of sumoylation are still controversial, acetylation modifies p53 interaction with chromatin embedded promoters, and enforces p53 apoptotic activity. In this study, we show that the N-terminal region of SUMO-1 might functionally mimic this activity of the p53 C-terminal tail. We found that this SUMO-1 domain possesses similarity with the C-terminal acetylable p53 tail as well as with acetylable domains of other transcription factors. SUMO-1 is, indeed, acetylated when conjugated to its substrates and to p53. In the acetylable form SUMO-1 tunes the p53 response by modifying p53 transcriptional program, by promoting binding onto selected promoters and by favoring apoptosis. By contrast, when non-acetylable, SUMO-1 enforces cell-cycle arrest and p53 binding to a different sets of genes. These data demonstrate for the first time that SUMO-1, a post-translational modification is, in turn, modified by acetylation. Further, they imply that the pleiotropy of effects by which SUMO-1 influences various cellular outcomes and the activity of p53 depends upon its acetylation state.

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Available from: Maria Laura Avantaggiati, Feb 22, 2014
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    • "While SUMO modifies HDAC- and HAT-containing complexes, SUMO itself is a substrate for acetylation. SUMO acetylation (Ac) has been reported to mimic acetylation of the TF modified by Ac-SUMO (Cheema et al., 2010). SUMO acetylation neutralizes the basic charges that surround the SIM docking site and, most remarkably, prevents SUMO-SIM interactions (Ullmann et al., 2012; Figure 1B). "
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    ABSTRACT: Small Ubiquitin-like MOdifier (SUMO) is a key regulator of abiotic stress, disease resistance, and development in plants. The identification of >350 plant SUMO targets has revealed many processes modulated by SUMO and potential consequences of SUMO on its targets. Importantly, highly related proteins are SUMO-modified in plants, yeast, and metazoans. Overlapping SUMO targets include heat-shock proteins (HSPs), transcription regulators, histones, histone-modifying enzymes, proteins involved in DNA damage repair, but also proteins involved in mRNA biogenesis and nucleo-cytoplasmic transport. Proteomics studies indicate key roles for SUMO in gene repression by controlling histone (de)acetylation activity at genomic loci. The responsible heavily sumoylated transcriptional repressor complexes are recruited by plant transcription factors (TFs) containing an (ERF)-associated Amphiphilic Repression (EAR) motif. These TFs are not necessarily themselves a SUMO target. Conversely, SUMO acetylation (Ac) prevents binding of downstream partners by blocking binding of their SUMO-interaction peptide motifs to Ac-SUMO. In addition, SUMO acetylation has emerged as a mechanism to recruit specifically bromodomains. Bromodomains are generally linked with gene activation. These findings strengthen the idea of a bi-directional sumo-acetylation switch in gene regulation. Quantitative proteomics has highlighted that global sumoylation provides a dynamic response to protein damage involving SUMO chain-mediated protein degradation, but also SUMO E3 ligase-dependent transcription of HSP genes. With these insights in SUMO function and novel technical advancements, we can now study SUMO dynamics in responses to (a)biotic stress in plants.
    Frontiers in Plant Science 09/2012; 3:215. DOI:10.3389/fpls.2012.00215 · 3.95 Impact Factor
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    • "Acetylation of this residue was also found on endogenous SUMO2/3 conjugates, indicating that it occurs under physiological conditions (Figure S1B). Consistent with this finding, we have recently demonstrated acetylation of the corresponding residue K37 in SUMO1 using MS/MS and a K37 acetyl-specific antibody (Cheema et al., 2010). "
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    Molecular cell 05/2012; 46(6):759-70. DOI:10.1016/j.molcel.2012.04.006 · 14.02 Impact Factor
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    • "The amino acid residues that most often undergo the respective modifications in a given context have been highlighted. For details of posttranslational alterations in p53 refer to [113–127]. "
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    ABSTRACT: Posttranslational modifications (PTMs) modulate protein function in most eukaryotes and have a ubiquitous role in diverse range of cellular functions. Identification, characterization, and mapping of these modifications to specific amino acid residues on proteins are critical towards understanding their functional significance in a biological context. The interpretation of proteome data obtained from the high-throughput methods cannot be deciphered unambiguously without a priori knowledge of protein modifications. An in-depth understanding of protein PTMs is important not only for gaining a perception of a wide array of cellular functions but also towards developing drug therapies for many life-threatening diseases like cancer and neurodegenerative disorders. Many of the protein modifications like ubiquitination play a decisive role in various drug response(s) and eventually in disease prognosis. Thus, many commonly observed PTMs are routinely tracked as disease markers while many others are used as molecular targets for developing target-specific therapies. In this paper, we summarize some of the major, well-studied protein alterations and highlight their importance in various chronic diseases and normal development. In addition, other promising minor modifications such as SUMOylation, observed to impact cellular dynamics as well as disease pathology, are mentioned briefly.
    07/2011; 2011(2):207691. DOI:10.4061/2011/207691
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