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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / metabolism
  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded* / drug effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Mice
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism
  • Multiprotein Complexes / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Telomere / metabolism

Substances

  • BRCA1 Protein
  • Multiprotein Complexes
  • Poly(ADP-ribose) Polymerase Inhibitors