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

Mark S. Dunstan, Eva Barkauskaite, Pierre Lafite, Claire E. Knezevic, Amy Brassington, Marijan Ahel, Paul J. Hergenrother, David Leys () and Ivan Ahel ()
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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

Nature Communications, 2012, vol. 3, issue 1, 1-6

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1889

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