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

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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

2211-1247

Publisher:

Cell Press

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

20 May 2019 16:17

Last Modified:

20 May 2019 16:26

Publisher DOI:

10.1016/j.celrep.2018.04.046

PubMed ID:

29768208

Uncontrolled Keywords:

BRCA1 CST complex CTC1 DNA end resection PARP inhibitor STN1 TEN1 breast cancer drug resistance genetically engineered mouse model

BORIS DOI:

10.7892/boris.127534

URI:

https://boris.unibe.ch/id/eprint/127534

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