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Lookup NU author(s): Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019 The Authors. Published under the terms of the CC BY 4.0 license 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 H 2 O 2 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.
Author(s): Keuss MJ, Hjerpe R, Hsia O, Gourlay R, Burchmore R, Trost M, Kurz T
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Print publication date: 15/03/2019
Online publication date: 25/02/2019
Acceptance date: 28/01/2019
Date deposited: 19/03/2019
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: Wiley-VCH Verlag
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