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Cell Rep. 2018 May 15;23(7):2107-2118. doi: 10.1016/j.celrep.2018.04.046.

The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.

Author information

1
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
2
The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
3
Division of Oncogenomics, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
4
Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
5
Department of Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
6
Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
7
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
8
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
9
Department of Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
10
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands. Electronic address: j.jonkers@nki.nl.
11
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland. Electronic address: sven.rottenberg@vetsuisse.unibe.ch.

Abstract

Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1-independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells. Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause PARPi resistance in BRCA1-deficient cells in vitro and in vivo. We show that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. These data suggest that, in addition to its role in protecting telomeres, the CST complex also contributes to protecting DSBs from end resection.

KEYWORDS:

BRCA1; CST complex; CTC1; DNA end resection; PARP inhibitor; STN1; TEN1; breast cancer; drug resistance; genetically engineered mouse model

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