5lhb
POLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017262
Structural highlights
FunctionPARG_HUMAN Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.[1] Publication Abstract from PubMedThe enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity. Using one of these tool compounds, we demonstrate pharmacology consistent with PARG inhibition. Further, while the roles of PARG and poly(ADP-ribose) polymerase (PARP) are closely intertwined, we demonstrate that the pharmacology of a PARG inhibitor differs from that observed with the more thoroughly studied PARP inhibitor olaparib. We believe that these tools will facilitate a wider understanding of this important component of DNA repair and may enable the development of novel therapeutic agents exploiting the critical dependence of tumors on the DNA damage response (DDR). First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib.,James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ ACS Chem Biol. 2016 Oct 12. PMID:27689388[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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