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Keuss, Matthew J; Hjerpe, Roland; Hsia, Oliver; Gourlay, Robert; Burchmore, Richard; Trost, Matthias; Kurz, Thimo
The EMBO journal, 15 March 2019, Volume: 38, Issue: 6Journal Article
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. Synopsis Cullin‐independent physiological roles of NEDD8, a ubiquitin‐like modifier, have remained elusive. Oxidative stress or deletion of deneddylase NEDP1 both induce chain formation of endogenous NEDD8, with tri‐NEDD8 binding and inhibition cellular poly(ADP‐ribose) polymerase. NEDP1 deletion results in the accumulation of NEDD8 chains. NEDD8 chains accumulate following oxidative stress in wild‐type cells. NEDP1 deletion protects from PARP‐1‐mediated cell death after oxidative stress. Unanchored NEDD8 trimers bind the second zinc finger domain of PARP‐1 to limit its activation. Acetylation of NEDD8 trimers modulates binding and inhibition of PARP‐1. Reactive oxygen species or deletion of deneddylase NEDP1 both induce accumulation of endogenous NEDD8 chains, some of which bind to and inhibit poly(ADP‐ribose) polymerase 1.
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