Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation.
BACKGROUND
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-kappaB 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.


RESULTS
By 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-kappaB by TNF-alpha and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells.


CONCLUSIONS
This is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications.
Scheper
Johanna
J
Department of Cell Biology, Institute for Molecular Biology (IBMB-CSIC), Barcelona, Spain.
Guerra-Rebollo
Marta
M
Sanclimens
Glòria
G
Moure
Alejandra
A
Masip
Isabel
I
González-Ruiz
Domingo
D
Rubio
Nuria
N
Crosas
Bernat
B
Meca-Cortés
Oscar
O
Loukili
Noureddine
N
Plans
Vanessa
V
Morreale
Antonio
A
Blanco
Jerónimo
J
Ortiz
Angel R
AR
Messeguer
Angel
A
Thomson
Timothy M
TM
D000818:Animals; D002384:Catalysis; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D054875:Ubiquitination
D016328:NF-kappa B; D011506:Proteins