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Highly specific intracellular ubiquitination of a small molecule.
Li, Weicheng; Garcia-Rivera, Enrique M; Mitchell, Dylan C; Chick, Joel M; Maetani, Micah; Knapp, John M; Matthews, Geoffrey M; Shirasaki, Ryosuke; de Matos Simoes, Ricardo; Viswanathan, Vasanthi; Pulice, John L; Rees, Matthew G; Roth, Jennifer A; Gygi, Steven P; Mitsiades, Constantine S; Kadoch, Cigall; Schreiber, Stuart L; Ostrem, Jonathan M L.
Affiliation
  • Li W; Department of Medicine, University of California, San Francisco; San Francisco, CA 94158, USA.
  • Garcia-Rivera EM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
  • Mitchell DC; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Chick JM; Department of Cell Biology, Harvard Medical School; Boston, MA 02115, USA.
  • Maetani M; Department of Cell Biology, Harvard Medical School; Boston, MA 02115, USA.
  • Knapp JM; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Matthews GM; Department of Chemistry and Chemical Biology, Harvard University; Cambridge, MA 02138, USA.
  • Shirasaki R; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • de Matos Simoes R; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
  • Viswanathan V; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
  • Pulice JL; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
  • Rees MG; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Roth JA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
  • Gygi SP; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Mitsiades CS; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Kadoch C; Broad Institute of MIT and Harvard; Cambridge, MA 02215, USA.
  • Schreiber SL; Department of Cell Biology, Harvard Medical School; Boston, MA 02115, USA.
  • Ostrem JML; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School; Boston, MA 02215, USA.
bioRxiv ; 2024 Jan 28.
Article in En | MEDLINE | ID: mdl-38328167
ABSTRACT
Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here, we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains causing broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent upon two homologous E3 ubiquitin ligases, RNF19A and RNF19B. Our finding opens the possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule, and more broadly raises the potential for posttranslational modification in trans.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2024 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2024 Document type: Article Affiliation country: Estados Unidos