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Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities

Author

Listed:
  • Eva Barkauskaite

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

  • Amy Brassington

    (Manchester Institute of Biotechnology, University of Manchester)

  • Edwin S. Tan

    (Harvard Medical School WA 536)

  • Jim Warwicker

    (Manchester Institute of Biotechnology, University of Manchester)

  • Mark S. Dunstan

    (Manchester Institute of Biotechnology, University of Manchester)

  • Benito Banos

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

  • Pierre Lafite

    (Institut de Chimie Organique et Analytique, Université d’Orléans—CNRS—UMR 7311 BP6769 Rue de Chartres)

  • Marijan Ahel

    (Rudjer Boskovic Institute)

  • Timothy J. Mitchison

    (Harvard Medical School WA 536)

  • Ivan Ahel

    (Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester
    Sir William Dunn School of Pathology, University of Oxford)

  • David Leys

    (Manchester Institute of Biotechnology, University of Manchester)

Abstract

Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer is catalysed by poly(ADP-ribose) glycohydrolase (PARG), whose endo-glycohydrolase activity generates PAR fragments. Here we present the crystal structure of PARG incorporating the PAR substrate. The two terminal ADP-ribose units of the polymeric substrate are bound in exo-mode. Biochemical and modelling studies reveal that PARG acts predominantly as an exo-glycohydrolase. This preference is linked to Phe902 (human numbering), which is responsible for low-affinity binding of the substrate in endo-mode. Our data reveal the mechanism of poly-ADP-ribosylation reversal, with ADP-ribose as the dominant product, and suggest that the release of apoptotic PAR fragments occurs at unusual PAR/PARG ratios.

Suggested Citation

  • Eva Barkauskaite & Amy Brassington & Edwin S. Tan & Jim Warwicker & Mark S. Dunstan & Benito Banos & Pierre Lafite & Marijan Ahel & Timothy J. Mitchison & Ivan Ahel & David Leys, 2013. "Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities," Nature Communications, Nature, vol. 4(1), pages 1-8, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3164
    DOI: 10.1038/ncomms3164
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    Cited by:

    1. Edoardo José Longarini & Ivan Matić, 2024. "Preserving ester-linked modifications reveals glutamate and aspartate mono-ADP-ribosylation by PARP1 and its reversal by PARG," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Tong Wang & Kush Coshic & Mohsen Badiee & Maranda R. McDonald & Aleksei Aksimentiev & Lois Pollack & Anthony K. L. Leung, 2024. "Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose)," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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