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Mol Cell. 2018 Dec 20;72(6):925-941.e4. doi: 10.1016/j.molcel.2018.10.045.

USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors.

Author information

1
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
3
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Box 357280, Seattle, WA, USA.
5
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.

Abstract

BRCA1-deficient tumor cells have defects in homologous-recombination repair and replication fork stability, resulting in PARP inhibitor sensitivity. Here, we demonstrate that a deubiquitinase, USP1, is upregulated in tumors with mutations in BRCA1. Knockdown or inhibition of USP1 resulted in replication fork destabilization and decreased viability of BRCA1-deficient cells, revealing a synthetic lethal relationship. USP1 binds to and is stimulated by fork DNA. A truncated form of USP1, lacking its DNA-binding region, was not stimulated by DNA and failed to localize and protect replication forks. Persistence of monoubiquitinated PCNA at the replication fork was the mechanism of cell death in the absence of USP1. Taken together, USP1 exhibits DNA-mediated activation at the replication fork, protects the fork, and promotes survival in BRCA1-deficient cells. Inhibition of USP1 may be a useful treatment for a subset of PARP-inhibitor-resistant BRCA1-deficient tumors with acquired replication fork stabilization.

KEYWORDS:

BRCA1; PCNA; UAF1; USP1; deubiquitinating enzymes; replication fork

PMID:
30576655
PMCID:
PMC6390489
[Available on 2019-12-20]
DOI:
10.1016/j.molcel.2018.10.045
[Indexed for MEDLINE]

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