The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.
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Date
2018-05-15Author
Barazas, M
Annunziato, S
Pettitt, SJ
de Krijger, I
Ghezraoui, H
Roobol, SJ
Lutz, C
Frankum, J
Song, FF
Brough, R
Evers, B
Gogola, E
Bhin, J
van de Ven, M
van Gent, DC
Jacobs, JJL
Chapman, R
Lord, CJ
Jonkers, J
Rottenberg, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Telomere
Animals
Mice
Disease Models, Animal
Multiprotein Complexes
BRCA1 Protein
Drug Resistance, Neoplasm
Female
DNA Breaks, Double-Stranded
CRISPR-Cas Systems
Poly(ADP-ribose) Polymerase Inhibitors
Mouse Embryonic Stem Cells
Research team
Gene Function
Language
eng
Date accepted
2018-04-11
License start date
2018-05
Citation
Cell reports, 2018, 23 (7), pp. 2107 - 2118
Publisher
CELL PRESS