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The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase

Author

Listed:
  • Dea Slade

    (Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester
    Université de Paris-Descartes, Faculté de Médecine, INSERM U1001, 156 rue de Vaugirard)

  • Mark S. Dunstan

    (Manchester Interdisciplinary Biocentre)

  • Eva Barkauskaite

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

  • Ria Weston

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

  • Pierre Lafite

    (ICOA – UMR CNRS 6005 Université d’Orléans, Rue de Chartres)

  • Neil Dixon

    (Manchester Interdisciplinary Biocentre)

  • Marijan Ahel

    (Rudjer Boskovic Institute, Bijenicka 54)

  • David Leys

    (Manchester Interdisciplinary Biocentre)

  • Ivan Ahel

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

Abstract

Taking PAR apart Proteins can be reversibly modified through the addition of repeating, polymerized ADP-ribose (PAR) subunits catalysed by poly(ADP-ribose) polymerase (PARP). Removal of PAR requires a glycohydrolase (PARG), which cleaves the ribose–ribose bond between subunits. Ivan Ahel and colleagues report that bacteria and fungi have a divergent PARG, which is unrelated to other enzymes that cleave PAR. Its structure, in complex with ADP-ribose and with a PARG inhibitor, and the results of mutational analysis suggest that the mechanism used in mammals and bacteria may be conserved. PARP inhibitors are being developed as pharmaceuticals for diseases including cancer, and this work suggests that small, cell-permeable PARG inhibitors might also be possible drug candidates.

Suggested Citation

  • Dea Slade & Mark S. Dunstan & Eva Barkauskaite & Ria Weston & Pierre Lafite & Neil Dixon & Marijan Ahel & David Leys & Ivan Ahel, 2011. "The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase," Nature, Nature, vol. 477(7366), pages 616-620, September.
    • Handle: RePEc:nat:nature:v:477:y:2011:i:7366:d:10.1038_nature10404
    DOI: 10.1038/nature10404
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    Citations

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    Cited by:

    1. Zhengrui Zhang & Jiaqi Fu & Johannes Gregor Matthias Rack & Chuang Li & Jim Voorneveld & Dmitri V. Filippov & Ivan Ahel & Zhao-Qing Luo & Chittaranjan Das, 2024. "Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Ivo A. Hendriks & Sara C. Buch-Larsen & Evgeniia Prokhorova & Jonas D. Elsborg & Alexandra K.L.F.S. Rebak & Kang Zhu & Dragana Ahel & Claudia Lukas & Ivan Ahel & Michael L. Nielsen, 2021. "The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Marie-France Langelier & Ramya Billur & Aleksandr Sverzhinsky & Ben E. Black & John M. Pascal, 2021. "HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. 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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