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PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359.

ABSTRACT: 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.

SUBMITTER: Rodriguez J

PROVIDER: S-EPMC6088137 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359.

Rodriguez Javier J Herrero Ana A Li Shuijie S Rauch Nora N Quintanilla Andrea A Wynne Kieran K Krstic Aleksandar A Acosta Juan Carlos JC Taylor Cormac C Schlisio Susanne S von Kriegsheim Alex A

Cell reports 20180701 5

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 wit ...[more]

PMID: 30067985

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