Barkauskaite, EvaBrassington, AmyTan, Edwin S.Warwicker, JimDunstan, Mark S.Banos, BenitoLafite, PierreAhel, MarijanMitchison, TimothyAhel, IvanLeys, David2014-03-012013Barkauskaite, E., A. Brassington, E. S. Tan, J. Warwicker, M. S. Dunstan, B. Banos, P. Lafite, et al. 2013. “Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities.” Nature Communications 4 (1): 2164. doi:10.1038/ncomms3164. http://dx.doi.org/10.1038/ncomms3164.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:11855826Poly-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.en-USJournal Article2014-03-0110.1038/ncomms3164