PHD3 regulates p53 protein stability by hydroxylating Proline 359

Javier Rodriguez; Ana Herrero; Shuijie Li; Nora Rauch; Andrea Quintanilla; Kieran Wynne; Aleksander Krstic; Juan Carlos Acosta; Cormac Taylor; Susanne Schlisio; Alex von Kriegsheim

doi:10.1016/j.celrep.2018.06.108

PHD3 regulates p53 protein stability by hydroxylating Proline 359

Javier Rodriguez, Ana Herrero, Shuijie Li, Nora Rauch, Andrea Quintanilla, Kieran Wynne, Aleksander Krstic, Juan Carlos Acosta, Cormac Taylor, Susanne Schlisio, Alex von Kriegsheim

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Cellular p53 protein levels are regulated by an ubiquitination/de-ubiquitination cycle which can target the protein for proteasomal destruction. The ubiquitination reaction is catalysed 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.

Original language	English
Journal	Cell Reports
DOIs	https://doi.org/10.1016/j.celrep.2018.06.108
Publication status	Published - 31 Jul 2018

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10.1016/j.celrep.2018.06.108

1-s2.0-S2211124718310507-mainFinal published version, 3.91 MBLicence: CC BY

High resolution metabolite and peptide mass spectrometry
Von Kriegsheim, A., Christophorou, M., Finch, A., Morton, N., Ponting, C. & Walmsley, S.
UK-based charities
2/10/17 → 1/11/22
Project: Research
Cancer Research UK Edinburgh Centre Award 2017/2018
Frame, M. & Tomlinson, I.
UK-based charities
1/04/17 → 31/03/22
Project: Research

Alex Von Kriegsheim
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Cancer Network Biology
- Edinburgh Cancer Research Centre
Person: Academic: Research Active

Cite this

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title = "PHD3 regulates p53 protein stability by hydroxylating Proline 359",

abstract = "Cellular p53 protein levels are regulated by an ubiquitination/de-ubiquitination cycle which can target the protein for proteasomal destruction. The ubiquitination reaction is catalysed 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.",

author = "Javier Rodriguez and Ana Herrero and Shuijie Li and Nora Rauch and Andrea Quintanilla and Kieran Wynne and Aleksander Krstic and Acosta, {Juan Carlos} and Cormac Taylor and Susanne Schlisio and {von Kriegsheim}, Alex",

year = "2018",

month = jul,

day = "31",

doi = "10.1016/j.celrep.2018.06.108",

language = "English",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

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TY - JOUR

T1 - PHD3 regulates p53 protein stability by hydroxylating Proline 359

AU - Rodriguez, Javier

AU - Herrero, Ana

AU - Li, Shuijie

AU - Rauch, Nora

AU - Quintanilla, Andrea

AU - Wynne, Kieran

AU - Krstic, Aleksander

AU - Acosta, Juan Carlos

AU - Taylor, Cormac

AU - Schlisio, Susanne

AU - von Kriegsheim, Alex

PY - 2018/7/31

Y1 - 2018/7/31

N2 - Cellular p53 protein levels are regulated by an ubiquitination/de-ubiquitination cycle which can target the protein for proteasomal destruction. The ubiquitination reaction is catalysed 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.

AB - Cellular p53 protein levels are regulated by an ubiquitination/de-ubiquitination cycle which can target the protein for proteasomal destruction. The ubiquitination reaction is catalysed 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.

U2 - 10.1016/j.celrep.2018.06.108

DO - 10.1016/j.celrep.2018.06.108

M3 - Article

SN - 2211-1247

JO - Cell Reports

JF - Cell Reports

ER -

PHD3 regulates p53 protein stability by hydroxylating Proline 359

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Projects

High resolution metabolite and peptide mass spectrometry

Cancer Research UK Edinburgh Centre Award 2017/2018

Profiles

Alex Von Kriegsheim

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