The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.
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Embargo End Date
ICR Authors
Authors
Barazas, M
Annunziato, S
Pettitt, SJ
de Krijger, I
Ghezraoui, H
Roobol, SJ
Lutz, C
Frankum, J
Song, FF
Brough, R
Evers, B
Gogola, E
Bhin, J
van de Ven, M
van Gent, DC
Jacobs, JJL
Chapman, R
Lord, CJ
Jonkers, J
Rottenberg, S
Annunziato, S
Pettitt, SJ
de Krijger, I
Ghezraoui, H
Roobol, SJ
Lutz, C
Frankum, J
Song, FF
Brough, R
Evers, B
Gogola, E
Bhin, J
van de Ven, M
van Gent, DC
Jacobs, JJL
Chapman, R
Lord, CJ
Jonkers, J
Rottenberg, S
Document Type
Journal Article
Date
2018-05-15
Date Accepted
2018-04-11
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.
Citation
Cell reports, 2018, 23 (7), pp. 2107 - 2118
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Gene Function