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 |
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Rok vydání: | 2019 |
Předmět: |
DNA Replication
0301 basic medicine Cell biology 030103 biophysics Glycoside Hydrolases Molecular biology DNA damage Science Poly ADP ribose polymerase Cell Biophysics General Physics and Astronomy Article General Biochemistry Genetics and Molecular Biology Small Molecule Libraries Poly ADP Ribosylation 03 medical and health sciences PARP1 Cell Line Tumor Neoplasms medicine Humans Enzyme Inhibitors lcsh:Science Polymerase Cancer PARG Multidisciplinary Cell Death biology Drug discovery Chemistry General Chemistry 3. Good health 030104 developmental biology medicine.anatomical_structure Cell culture Cancer cell biology.protein lcsh:Q Poly(ADP-ribose) Polymerases |
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 |
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