Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

Research output: Contribution to journalJournal articleResearchpeer-review

  • Evgeniia Prokhorova
  • Thomas Agnew
  • Anne R Wondisford
  • Michael Tellier
  • Nicole Kaminski
  • Danique Beijer
  • James Holder
  • Josephine Groslambert
  • Marcin J Suskiewicz
  • Kang Zhu
  • Julia M Reber
  • Sarah C Krassnig
  • Luca Palazzo
  • Shona Murphy
  • Nielsen, Michael Lund
  • Aswin Mangerich
  • Dragana Ahel
  • Jonathan Baets
  • Roderick J O'Sullivan
  • Ivan Ahel

ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.

Original languageEnglish
JournalMolecular Cell
Issue number12
Pages (from-to)2640-2655
Publication statusPublished - 2021

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