Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Autor: Albino Bacolla, N. Babu Chinnam, L.S. Warden, Daniel J. Laverty, C.A. Brosey, L.P.F. Balapiti-Modarage, Davide Moiani, Roderick A. Stegeman, Zu Ye, B.L. Walker, Yasin Pourfarjam, In-Kwon Kim, Sarita Namjoshi, Zamal Ahmed, Darin E. Jones, J.H. Houl, Tom Ellenberger, Mei-Kuang Chen, John A. Tainer, Mien Chie Hung, Zachary D. Nagel
Rok vydání: 2019
Předmět:
Zdroj: Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019)
Nature Communications
ISSN: 2041-1723
Popis: Poly(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.
PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.
Databáze: OpenAIRE