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, David Leys

Research output: Contribution to journalArticlepeer-review

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. © 2013 Macmillan Publishers Limited. All rights reserved.
Original languageEnglish
Article number2164
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 2013

Fingerprint

Dive into the research topics of 'Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities'. Together they form a unique fingerprint.

Cite this