The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells
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 suc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2018
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| _version_ | 1826298086614368256 |
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| author | Barazas, M Annunziato, S Pettitt, S de Krijger, I Ghezraoui, H Roobol, S Lutz, C Frankum, J Song, F Brough, R Evers, B Gogola, E Bhin, J van de Ven, M van Gent, D Jacobs, J Chapman, J Lord, C Jonkers, J Rottenberg, S |
| author_facet | Barazas, M Annunziato, S Pettitt, S de Krijger, I Ghezraoui, H Roobol, S Lutz, C Frankum, J Song, F Brough, R Evers, B Gogola, E Bhin, J van de Ven, M van Gent, D Jacobs, J Chapman, J Lord, C Jonkers, J Rottenberg, S |
| author_sort | Barazas, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:41:28Z |
| format | Journal article |
| id | oxford-uuid:d1ccdf9b-044a-4271-b438-e7a58848d6e3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:41:28Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:d1ccdf9b-044a-4271-b438-e7a58848d6e32022-03-27T07:59:28ZThe CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d1ccdf9b-044a-4271-b438-e7a58848d6e3EnglishSymplectic Elements at OxfordElsevier2018Barazas, MAnnunziato, SPettitt, Sde Krijger, IGhezraoui, HRoobol, SLutz, CFrankum, JSong, FBrough, REvers, BGogola, EBhin, Jvan de Ven, Mvan Gent, DJacobs, JChapman, JLord, CJonkers, JRottenberg, SSelective 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. |
| spellingShingle | Barazas, M Annunziato, S Pettitt, S de Krijger, I Ghezraoui, H Roobol, S Lutz, C Frankum, J Song, F Brough, R Evers, B Gogola, E Bhin, J van de Ven, M van Gent, D Jacobs, J Chapman, J Lord, C Jonkers, J Rottenberg, S The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title | The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title_full | The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title_fullStr | The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title_full_unstemmed | The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title_short | The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells |
| title_sort | cst complex mediates end protection at double strand breaks and promotes parp inhibitor sensitivity in brca1 deficient cells |
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