6oak | pdb_00006oak
Structure of human PARG complexed with JA2131
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 PubMedPoly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death.,Houl JH, Ye Z, Brosey CA, Balapiti-Modarage LPF, Namjoshi S, Bacolla A, Laverty D, Walker BL, Pourfarjam Y, Warden LS, Babu Chinnam N, Moiani D, Stegeman RA, Chen MK, Hung MC, Nagel ZD, Ellenberger T, Kim IK, Jones DE, Ahmed Z, Tainer JA Nat Commun. 2019 Dec 11;10(1):5654. doi: 10.1038/s41467-019-13508-4. PMID:31827085[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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