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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BRCA1, CST complex, CTC1, DNA end resection, PARP inhibitor, STN1, TEN1, breast cancer, drug resistance, genetically engineered mouse model, Animals, BRCA1 Protein, CRISPR-Cas Systems, Cell Line, Tumor, DNA Breaks, Double-Stranded, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Mice, Mouse Embryonic Stem Cells, Multiprotein Complexes, Poly(ADP-ribose) Polymerase Inhibitors, Telomere