The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells
| Autor: | Stefano Annunziato, Jinhyuk Bhin, Marieke van de Ven, Rachel Brough, Bastiaan Evers, Marco Barazas, Catrin Lutz, Stephen J. Pettitt, Dik C. van Gent, Jacqueline J.L. Jacobs, Stefan J. Roobol, Jessica Frankum, Jos Jonkers, Inge de Krijger, Hind Ghezraoui, Fei Fei Song, Christopher J. Lord, J. Ross Chapman, Ewa Gogola, Sven Rottenberg |
|---|---|
| Přispěvatelé: | Molecular Genetics, Radiology & Nuclear Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA end resection Poly ADP ribose polymerase 610 Medicine & health Synthetic lethality CST complex Poly(ADP-ribose) Polymerase Inhibitors General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound Mice breast cancer Cell Line Tumor Animals DNA Breaks Double-Stranded Polymerase drug resistance biology 630 Agriculture Chemistry TEN1 BRCA1 Protein Mouse Embryonic Stem Cells Telomere BRCA1 genetically engineered mouse model 3. Good health Cell biology Disease Models Animal 030104 developmental biology PARP inhibitor STN1 Drug Resistance Neoplasm Multiprotein Complexes biology.protein 570 Life sciences CTC1 Female CRISPR-Cas Systems Homologous recombination DNA |
| Zdroj: | Barazas, Marco; Annunziato, Stefano; Pettitt, Stephen J; de Krijger, Inge; Ghezraoui, Hind; Roobol, Stefan J; Lutz, Catrin; Frankum, Jessica; Song, Fei Fei; Brough, Rachel; Evers, Bastiaan; Gogola, Ewa; Bhin, Jinhyuk; van de Ven, Marieke; van Gent, Dik C; Jacobs, Jacqueline J L; Chapman, Ross; Lord, Christopher J; Jonkers, Jos and Rottenberg, Sven (2018). The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells. Cell reports, 23(7), pp. 2107-2118. Cell Press 10.1016/j.celrep.2018.04.046 Cell Reports Cell Reports, 23(7), 2107-2118. Cell Press |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2018.04.046 |
| Popis: | Summary 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. Graphical Abstract Highlights • PARP inhibitor resistance screens independently identify loss of CTC1 as major hit • The CST complex promotes PARP inhibitor sensitivity in BRCA1-deficient cells • Depletion of CTC1 restores end resection in BRCA1-deficient cells • CTC1 facilitates double-strand break repair via canonical non-homologous end joining 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|