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

Eva Barkauskaite, Amy Brassington, Edwin S. Tan, Jim Warwicker, Mark S. Dunstan, Benito Banos, Pierre Lafite, Marijan Ahel, Timothy J. Mitchison, Ivan Ahel () and David Leys ()
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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
David Leys: Manchester Institute of Biotechnology, University of Manchester

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3164

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