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. Using CRISPR/SpCas9-based loss-of-function screens, Barazas et al. show that loss of the CTC1-STN1-TEN1 (CST) complex promotes PARP inhibitor resistance in BRCA1-deficient cells. Mechanistically, the CST complex maintains double-strand break end stability in addition to its role in protecting telomeric ends.

Additional Metadata
Keywords BRCA1, breast cancer, CST complex, CTC1, DNA end resection, drug resistance, genetically engineered mouse model, PARP inhibitor, STN1, TEN1
Persistent URL dx.doi.org/10.1016/j.celrep.2018.04.046, hdl.handle.net/1765/106351
Journal Cell Reports
Citation
Barazas, M, Annunziato, S. (Stefano), Pettitt, S.J. (Stephen J.), de Krijger, I. (Inge), Ghezraoui, H. (Hind), Roobol, S.J. (Stefan J.), … Rottenberg, S. (2018). The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells. Cell Reports. doi:10.1016/j.celrep.2018.04.046