Open AccessPHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359
Author(s) -
Javier Rodríguez,
Ana Herrero,
Shuijie Li,
Nora Rauch,
Andrea Quintanilla,
Kieran Wynne,
Aleksandar Krstić,
Juan Carlos Acosta,
Cormac T. Taylor,
Susanne Schlisio,
Alex von Kriegsheim
Publication year - 2018
Publication title -
cell reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.264
H-Index - 154
eISSN - 2639-1856
pISSN - 2211-1247
DOI - 10.1016/j.celrep.2018.06.108
Subject(s) - deubiquitinating enzyme , ubiquitin , hydroxylation , microbiology and biotechnology , proline , lysine , biochemistry , ubiquitin ligase , chemistry , biology , enzyme , gene , amino acid
Cellular p53 protein levels are regulated by a ubiquitination/de-ubiquitination cycle that can target the protein for proteasomal destruction. The ubiquitination reaction is catalyzed by a multitude of ligases, whereas the removal of ubiquitin chains is mediated by two deubiquitinating enzymes (DUBs), USP7 (HAUSP) and USP10. Here, we show that PHD3 hydroxylates p53 at proline 359, a residue that is in the p53-DUB binding domain. Hydroxylation of p53 upon proline 359 regulates its interaction with USP7 and USP10, and its inhibition decreases the association of p53 with USP7/USP10, increases p53 ubiquitination, and rapidly reduces p53 protein levels independently of mRNA expression. Our results show that p53 is a PHD3 substrate and that hydroxylation by PHD3 regulates p53 protein stability through modulation of ubiquitination.
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