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Updated: Feb 27, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Synergistic Cellular Toxicity from Inhibition of Poly(ADP-ribose) Glycohydrolase (PARG) and Ubiquitin-Specific

Stefan M Leonard1, Charlotte R Pearson1, Wynand P Roos1

  • 1Department of Pathology and Laboratory Medicine, Legorreta Cancer Center, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.

Toxics
|February 26, 2026
PubMed

Insights

Combining USP1 and PARG inhibitors shows synergistic effects in cancer treatment. This approach increases DNA damage markers and cell death, offering new therapeutic strategies for PARP inhibitor-resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ubiquitin-specific protease 1 (USP1) is a deubiquitylating enzyme crucial for DNA repair and synthesis.
  • USP1 targets proteins like FANCD2, PARP1, and PCNA, influencing DNA polymerase activity.
  • USP1 inhibitors (USP1i) show synthetic lethality with PARP inhibitors (PARPi) in certain cancers.

Purpose of the Study:

  • To investigate the relationship between USP1 inhibition and poly(ADP-ribose) glycohydrolase (PARG) inhibition.
  • To determine the combined effects of USP1 and PARG inhibition on cellular processes and cytotoxicity.

Main Methods:

  • Cell cytotoxicity and synergy assays were performed.
  • Analysis of PCNA-ubiquitin levels and poly(ADP-ribose) (PAR) accumulation was conducted.
  • Experiments utilized ML323 (USP1i) and PDD00017273 (PARGi).

Main Results:

  • Combined USP1 and PARG inhibition resulted in increased mono-ubiquitinated PCNA.
  • PAR accumulation was decreased under combined inhibition.
  • Synergistic cytotoxicity was observed between ML323 and PDD00017273.

Conclusions:

  • PARG inhibition combined with USP1 inhibition exhibits synergistic cytotoxicity.
  • This combination impacts PAR/ubiquitin dynamics and PCNA ubiquitination.
  • Further research is warranted to elucidate the mechanisms of USP1/PARG synthetic lethality and cell death.
Keywords:
PARGPARP1USP1poly(ADP-ribose)ubiquitin

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