MYB regulates the SUMO protease SENP1 and its novel interaction partner UXT, modulating MYB target genes and the SUMO landscape.

Autor:	Lemma RB; Department of Biosciences, University of Oslo, Oslo, Norway; Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo, Norway. Electronic address: r.b.lemma@ncmm.uio.no., Ledsaak M; Department of Biosciences, University of Oslo, Oslo, Norway; Faculty of Medicine, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Fuglerud BM; Department of Biosciences, University of Oslo, Oslo, Norway., Rodríguez-Castañeda F; Department of Biosciences, University of Oslo, Oslo, Norway., Eskeland R; Department of Biosciences, University of Oslo, Oslo, Norway; Faculty of Medicine, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Faculty of Medicine, Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Gabrielsen OS; Department of Biosciences, University of Oslo, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Sep; Vol. 299 (9), pp. 105062. Date of Electronic Publication: 2023 Jul 17.
DOI:	10.1016/j.jbc.2023.105062
Abstrakt:	SUMOylation is a post-translational modification frequently found on nuclear proteins, including transcription factors (TFs) and coactivators. By controlling the activity of several TFs, SUMOylation may have far-reaching effects. MYB is an example of a developmental TF subjected to SUMO-mediated regulation, through both SUMO conjugation and SUMO binding. How SUMO affects MYB target genes is unknown. Here, we explored the global effect of reduced SUMOylation of MYB on its downstream gene programs. RNA-Seq in K562 cells after MYB knockdown and rescue with mutants having an altered SUMO status revealed a number of differentially regulated genes and distinct gene ontology term enrichments. Clearly, the SUMO status of MYB both quantitatively and qualitatively affects its regulome. The transcriptome data further revealed that MYB upregulates the SUMO protease SENP1, a key enzyme that removes SUMO conjugation from SUMOylated proteins. Given this role of SENP1 in the MYB regulome, we expanded the analysis, mapped interaction partners of SENP1, and identified UXT as a novel player affecting the SUMO system by acting as a repressor of SENP1. MYB inhibits the expression of UXT suggesting that MYB is able not only to control a specific gene program directly but also indirectly by affecting the SUMO landscape through SENP1 and UXT. These findings suggest an autoactivation loop whereby MYB, through enhancing SENP1 and reducing UXT, is itself being activated by a reduced level of repressive SUMOylation. We propose that overexpressed MYB, seen in multiple cancers, may drive this autoactivation loop and contribute to oncogenic activation of MYB. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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