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Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

Author

Listed:
  • Mark S. Dunstan

    (Manchester Interdisciplinary Biocentre)

  • Eva Barkauskaite

    (Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester)

  • Pierre Lafite

    (ICOA–UMR CNRS 7311 Université d'Orléans Rue de Chartres)

  • Claire E. Knezevic

    (University of Illinois at Urbana-Champaign)

  • Amy Brassington

    (Manchester Interdisciplinary Biocentre)

  • Marijan Ahel

    (Rudjer Boskovic Institute)

  • Paul J. Hergenrother

    (University of Illinois at Urbana-Champaign)

  • David Leys

    (Manchester Interdisciplinary Biocentre)

  • Ivan Ahel

    (Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester)

Abstract

Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1′′-2′) ribose–ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.

Suggested Citation

  • Mark S. Dunstan & Eva Barkauskaite & Pierre Lafite & Claire E. Knezevic & Amy Brassington & Marijan Ahel & Paul J. Hergenrother & David Leys & Ivan Ahel, 2012. "Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase," Nature Communications, Nature, vol. 3(1), pages 1-6, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1889
    DOI: 10.1038/ncomms1889
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    Cited by:

    1. Pietro Fontana & Sara C. Buch-Larsen & Osamu Suyari & Rebecca Smith & Marcin J. Suskiewicz & Kira Schützenhofer & Antonio Ariza & Johannes Gregor Matthias Rack & Michael L. Nielsen & Ivan Ahel, 2023. "Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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