The ubiquitin-protein ligase activity of Hdm2 is inhibited by nucleic acids.
The proto-oncoprotein Hdm2 is a member of the RING finger-type family of ubiquitin-protein ligases E3. The RING finger domain is assumed to mediate the specific interaction of an E3 with its cognate ubiquitin-conjugating enzyme E2, which catalyzes the covalent attachment of ubiquitin to substrate proteins. In addition, the RING finger domain of Hdm2 is involved in Hdm2 homooligomer formation and has the capacity to bind to RNA in a sequence-specific manner. Here we report that interaction with nucleic acids interferes with both Hdm2/Hdm2 complex formation and auto-ubiquitination of Hdm2 in vitro. Furthermore, although binding of Hdm2 to the tumor suppressor p53 is not inhibited by nucleic acids, Hdm2-mediated ubiquitination of p53 is significantly decreased. Taken together, these results provide the first example of an E3 whose activity can be regulated by direct interaction with nucleic acids.
Linares
Laëtitia K
LK
Center for Biochemistry, Faculty of Medicine, and Center for Molecular Medicine, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, Germany.
Scheffner
Martin
M
D001483:Base Sequence; D019281:Dimerization; D005982:Glutathione Transferase; D006801:Humans; D009687:Nuclear Proteins; D009696:Nucleic Acids / Q000494:pharmacology*; D011131:Polyribonucleotides / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D009687:Nuclear Proteins; D009696:Nucleic Acids; D011131:Polyribonucleotides; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D012313:RNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase