title: Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD.
abstract: 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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Cheema
authors.forename: Chad D
authors.initials: CD
authors.lastname: Knights
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Jason
authors.initials: J
authors.lastname: Catania
authors.forename: Ricardo
authors.initials: R
authors.lastname: Perez
authors.forename: Brigitte
authors.initials: B
authors.lastname: Simons
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Kolukula
authors.forename: Maddalena
authors.initials: M
authors.lastname: Tilli
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Furth
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
mesh_terms: D000107:Acetylation; D000230:Adenocarcinoma / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051379:Mice; D008822:Mice, Transgenic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D013365:Submandibular Gland Neoplasms / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D025842:SUMO-1 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
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