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USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

Anna Nespolo1, Linda Stefenatti1, Ilenia Pellarin1

  • 1Molecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano (PN), Italy.

Science Advances
|November 13, 2024
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective ovarian cancer treatments. Targeting the USP1/PARP1 interaction enhances cancer cell death, offering a new therapeutic strategy for both sensitive and resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • PARP inhibitors (PARPi) are crucial for treating ovarian cancer with homologous recombination (HR) deficiency.
  • PARPi function by trapping PARP1 on DNA and inhibiting its enzymatic activity (PARylation).
  • Mechanisms of PARP1 recruitment, trapping, and resistance to PARPi require further investigation.

Purpose of the Study:

  • To investigate the role of the deubiquitinase USP1 in regulating PARP1 activity and PARPi sensitivity.
  • To explore the USP1-PARP1 interaction as a potential therapeutic target in ovarian cancer.

Main Methods:

  • Molecular interaction studies between USP1 and PARP1.
  • Analysis of PARP1 ubiquitination and chromatin trapping.
  • Assessment of cell death and DNA damage in response to USP1/PARP1 blockade in platinum/PARPi-sensitive and -resistant ovarian cancer cells.

Main Results:

  • USP1 deubiquitinates PARP1, specifically removing K63-linked polyubiquitination.
  • USP1 regulates PARP1 chromatin trapping and PARylation activity, influencing sensitivity to PARPi.
  • Combined blockade of USP1 and PARP1 significantly enhances replicative stress, DNA damage, and cell death in both sensitive and resistant cells.

Conclusions:

  • The USP1-PARP1 axis is a key regulator of PARPi sensitivity in ovarian cancer.
  • Targeting USP1 and PARP1 concurrently presents a promising therapeutic strategy for ovarian cancer patients, including those with chemoresistance and regardless of HR status.

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