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

Author

Listed:
  • Jerry H. Houl

    (University of Texas MD Anderson Cancer Center)

  • Zu Ye

    (University of Texas MD Anderson Cancer Center)

  • Chris A. Brosey

    (University of Texas MD Anderson Cancer Center)

  • Lakshitha P. F. Balapiti-Modarage

    (The University of Arkansas at Little Rock
    The University of Arkansas for Medical Sciences)

  • Sarita Namjoshi

    (University of Texas MD Anderson Cancer Center)

  • Albino Bacolla

    (University of Texas MD Anderson Cancer Center)

  • Daniel Laverty

    (Harvard University, School of Public Health)

  • Brian L. Walker

    (The University of Arkansas at Little Rock
    The University of Arkansas for Medical Sciences)

  • Yasin Pourfarjam

    (University of Cincinnati)

  • Leslie S. Warden

    (University of Texas MD Anderson Cancer Center)

  • Naga Babu Chinnam

    (University of Texas MD Anderson Cancer Center
    UTHealth Graduate School of Biomedical Sciences)

  • Davide Moiani

    (University of Texas MD Anderson Cancer Center)

  • Roderick A. Stegeman

    (Washington University School of Medicine)

  • Mei-Kuang Chen

    (University of Texas MD Anderson Cancer Center
    UTHealth Graduate School of Biomedical Sciences)

  • Mien-Chie Hung

    (University of Texas MD Anderson Cancer Center
    China Medical University)

  • Zachary D. Nagel

    (Harvard University, School of Public Health)

  • Tom Ellenberger

    (Washington University School of Medicine)

  • In-Kwon Kim

    (University of Cincinnati
    Washington University School of Medicine)

  • Darin E. Jones

    (The University of Arkansas at Little Rock
    The University of Arkansas for Medical Sciences)

  • Zamal Ahmed

    (University of Texas MD Anderson Cancer Center)

  • John A. Tainer

    (University of Texas MD Anderson Cancer Center)

Abstract

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.

Suggested Citation

  • Jerry H. Houl & Zu Ye & Chris A. Brosey & Lakshitha P. F. Balapiti-Modarage & Sarita Namjoshi & Albino Bacolla & Daniel Laverty & Brian L. Walker & Yasin Pourfarjam & Leslie S. Warden & Naga Babu Chin, 2019. "Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13508-4
    DOI: 10.1038/s41467-019-13508-4
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    Cited by:

    1. Michael U. Musheev & Lars Schomacher & Amitava Basu & Dandan Han & Laura Krebs & Carola Scholz & Christof Niehrs, 2022. "Mammalian N1-adenosine PARylation is a reversible DNA modification," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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