2. Academic Validation
  3. Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

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

  • Mol Cell. 2021 Jun 17;81(12):2640-2655.e8. doi: 10.1016/j.molcel.2021.04.028.
Evgeniia Prokhorova 1,  Thomas Agnew 1,  Anne R Wondisford 2,  Michael Tellier 1,  Nicole Kaminski 2,  Danique Beijer 3,  James Holder 1,  Josephine Groslambert 1,  Marcin J Suskiewicz 1,  Kang Zhu 1,  Julia M Reber 4,  Sarah C Krassnig 4,  Luca Palazzo 1,  Shona Murphy 1,  Michael L Nielsen 5,  Aswin Mangerich 4,  Dragana Ahel 1,  Jonathan Baets 6,  Roderick J O'Sullivan 2,  Ivan Ahel 7
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • 2 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 4 Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
  • 5 Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 6 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 7 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. Electronic address: [email protected].
PMID: 34019811 DOI: 10.1016/j.molcel.2021.04.028
Abstract

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.

Keywords

ADP-ribosylation; ARH3/ADPRHL2; BRCA; DNA damage; PARG; PARP inhibitor; cancer; chromatin; neurodegeneration; telomere.

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