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

• Matthew J Keuss ^[3] ; Roland Hjerpe ^[3] ; Oliver Hsia ^[3] ; Robert Gourlay ^[1] ; Richard Burchmore ^[2] ; Matthias Trost ^[1] ; Thimo Kurz ^[3]
  1. [1] MRC Protein Phosphorylation and Ubiquitylation Unit

     MRC Protein Phosphorylation and Ubiquitylation Unit

     Reino Unido

     
  2. [2] University of Glasgow

     University of Glasgow

     Reino Unido

     
  3. [3] 1 Henry Wellcome Lab of Cell Biology College of Medical, Veterinary and Life Sciences Institute of Molecular, Cell and Systems Biology University of Glasgow Glasgow UK

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 6, 2019
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • 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.