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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
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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
Summary
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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