Abstract
BackgroundSeveral pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-κB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev.Methodology/Principal FindingsBy applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-κB by TNF-α and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells.Conclusions/SignificanceThis is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications.
Highlights
Modifications by ubiquitin control the fate and participation of proteins in fundamental biological processes [1]
The formation of this class of ‘‘non-canonical’’ polyubiquitin chains is mostly catalyzed by the heterodimeric ubiquitin conjugating enzyme formed by Ubc13 and a Uev protein, Uev1 or Uev2/Mms2 in higher eukaryotes, or Mms2 in the yeast S. cerevisiae [2,4,5]
We have developed small molecules that can effectively and selectively antagonize the Ubc13-Uev1 interaction and inhibit K63 polyubiquitylation in both yeast and mammalian cells, and we have shown that these compounds can be used in combination therapy schemes as antitumoral agents in cultured and animal models of cancer
Summary
Modifications by ubiquitin (ubiquitylation) control the fate and participation of proteins in fundamental biological processes [1]. Polyubiquitin chains based on K63 are not as efficiently recognized by the proteasome, and rather modify substrate proteins for interactions with other proteins that participate in signaling and other nonproteolytic processes [2,3] The formation of this class of ‘‘non-canonical’’ polyubiquitin chains is mostly catalyzed by the heterodimeric ubiquitin conjugating enzyme formed by Ubc and a Uev protein, Uev or Uev2/Mms in higher eukaryotes, or Mms in the yeast S. cerevisiae [2,4,5]. Several pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev
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