USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity
PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)-based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.
Authors
- Vincenzo Canzonieri (ORCID: https://orcid.org/0000-0001-6010-0976)
- Fabio Puglisi (ORCID: https://orcid.org/0000-0003-0573-4938)
- Sara Barozzi
- Fabrizio Orsenigo
- Milena Sabrina Nicoloso (ORCID: https://orcid.org/0000-0003-4231-9303)
- Gian Luca Rampioni Vinciguerra (ORCID: https://orcid.org/0000-0003-0739-1668)
- Javad Karimbayli (ORCID: https://orcid.org/0000-0003-3031-7917)
- Michele Bartoletti (ORCID: https://orcid.org/0000-0002-9631-5693)
- Barbara Belletti (ORCID: https://orcid.org/0000-0003-2249-0285)
- Ilenia Segatto (ORCID: https://orcid.org/0000-0001-5282-1028)
- Giorgio Giorda (ORCID: https://orcid.org/0000-0001-6386-3565)
- Ilenia Pellarin (ORCID: https://orcid.org/0000-0002-1041-1722)
- Gustavo Baldassarre (ORCID: https://orcid.org/0000-0002-9750-8825)
- Mónica Schiappacassi (ORCID: https://orcid.org/0000-0003-4804-4291)
- Maura Sonego (ORCID: https://orcid.org/0000-0002-9505-9771)
- Emilio Lucia (ORCID: https://orcid.org/0000-0001-6882-5613)
- Riccardo Spizzo (ORCID: https://orcid.org/0000-0001-7772-0960)
- Alice Gambelli (ORCID: https://orcid.org/0000-0003-0223-9798)
- Linda Stefenatti
- Sara D’Andrea
- Anna Nespolo (ORCID: https://orcid.org/0009-0009-0294-8667)
Institutions
- University of Udine (IT)
- University of Trieste (IT)
- IFOM (IT)
- National Cancer Institute (UA)
- Centro di Riferimento Oncologico (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1126/sciadv.adp6567
- Citations
- 15
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.24
Funders
- Ministero della Salute
- Alleanza Contro il Cancro