2. Academic Validation
  3. USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

  • Sci Adv. 2024 Nov 15;10(46):eadp6567. doi: 10.1126/sciadv.adp6567.
Anna Nespolo 1,  Linda Stefenatti 1,  Ilenia Pellarin 1,  Alice Gambelli 1,  Gian Luca Rampioni Vinciguerra 1,  Javad Karimbayli 1,  Sara Barozzi 2,  Fabrizio Orsenigo 2,  Riccardo Spizzo 1,  Milena S Nicoloso 1,  Ilenia Segatto 1,  Sara D'Andrea 1,  Michele Bartoletti 3,  Emilio Lucia 4,  Giorgio Giorda 4,  Vincenzo Canzonieri 5 6,  Fabio Puglisi 3 7,  Barbara Belletti 1,  Monica Schiappacassi 1,  Gustavo Baldassarre 1,  Maura Sonego 1
Affiliations

Affiliations

  • 1 Molecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano (PN), Italy.
  • 2 IFOM ETS, The AIRC Institute of Molecular Oncology, Milan (MI), Italy.
  • 3 Deparment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano (PN), Italy.
  • 4 Gynecological Surgery Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano (PN), Italy.
  • 5 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano (PN), Italy.
  • 6 Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste (TS), Italy.
  • 7 Department of Medicine, University of Udine, Udine (UD), Italy.
PMID: 39536107 DOI: 10.1126/sciadv.adp6567
Abstract

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.

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