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Unanchored tri‐NEDD8 inhibits PARP‐1 to protect from oxidative stress‐induced cell death

Keuss, Matthew J; Hjerpe, Roland; Hsia, Oliver; Gourlay, Robert; Burchmore, Richard; Trost, Matthias; Kurz, Thimo; (2019) Unanchored tri‐NEDD8 inhibits PARP‐1 to protect from oxidative stress‐induced cell death. The EMBO Journal , 38 (6) , Article e100024. 10.15252/embj.2018100024. Green open access

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Abstract

NEDD8 is a ubiquitin-like protein that activates cullin-RING E3 ubiquitin ligases (CRLs). Here, we identify a novel role for NEDD8 in regulating the activity of poly(ADP-ribose) polymerase 1 (PARP-1) in response to oxidative stress. We show that treatment of cells with H2O2 results in the accumulation of NEDD8 chains, likely by directly inhibiting the deneddylase NEDP1. One chain type, an unanchored NEDD8 trimer, specifically bound to the second zinc finger domain of PARP-1 and attenuated its activation. In cells in which Nedp1 is deleted, large amounts of tri-NEDD8 constitutively form, resulting in inhibition of PARP-1 and protection from PARP-1-dependent cell death. Surprisingly, these NEDD8 trimers are additionally acetylated, as shown by mass spectrometry analysis, and their binding to PARP-1 is reduced by the overexpression of histone de-acetylases, which rescues PARP-1 activation. Our data suggest that trimeric, acetylated NEDD8 attenuates PARP-1 activation after oxidative stress, likely to delay the initiation of PARP-1-dependent cell death.

Type: Article
Title: Unanchored tri‐NEDD8 inhibits PARP‐1 to protect from oxidative stress‐induced cell death
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.2018100024
Publisher version: https://doi.org/10.15252/embj.2018100024
Language: English
Additional information: © 2019 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords: cell death; NEDD8; oxidative stress; PARP-1; parthanatos
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10145080
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