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

被引：128

作者：

Barazas, Marco ^{[1
]}

Annunziato, Stefano ^{[1
]}

Pettitt, Stephen J. ^{[2
,3
]}

de Krijger, Inge ^{[4
]}

Ghezraoui, Hind ^{[5
]}

Roobol, Stefan J. ^{[6
,7
]}

Lutz, Catrin ^{[1
]}

Frankum, Jessica ^{[2
,3
]}

Song, Fei Fei ^{[2
,3
]}

Brough, Rachel ^{[2
,3
]}

Evers, Bastiaan ^{[8
]}

Gogola, Ewa ^{[1
]}

Bhin, Jinhyuk ^{[1
,8
]}

van de Ven, Marieke ^{[1
,9
]}

van Gent, Dik C. ^{[6
]}

Jacobs, Jacqueline J. L. ^{[4
]}

Chapman, Ross ^{[5
]}

Lord, Christopher J. ^{[2
,3
]}

Jonkers, Jos ^{[1
]}

Rottenberg, Sven ^{[1
,10
]}

机构：

[1] Netherlands Canc Inst, Oncode Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands

[2] Inst Canc Res, CRUK Gene Funct Lab, London SW3 6JB, England

[3] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London SW3 6JB, England

[4] Netherlands Canc Inst, Div Oncogen, NL-1066 CX Amsterdam, Netherlands

[5] Univ Oxford, Wellcome Ctr Human Genet, Genome Integr Lab, Oxford OX3 7BN, England

[6] Erasmus Univ, Med Ctr, Dept Genet, Rotterdam, Netherlands

[7] Erasmus Univ, Med Ctr, Dept Radiol & Nucl Med, Rotterdam, Netherlands

[8] Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[9] Netherlands Canc Inst, Preclin Intervent Unit, Mouse Clin Canc & Aging Res MCCA, NL-1066 CX Amsterdam, Netherlands

[10] Univ Bern, Vetsuisse Fac, Inst Anim Pathol, Bern, Switzerland

来源：

CELL REPORTS | 2018年 / 23卷 / 07期

基金：

欧洲研究理事会; 瑞士国家科学基金会;

关键词：

METASTATIC PROSTATE-CANCER; DNA-DAMAGE RESPONSE; MAMMARY-TUMORS; HOMOLOGOUS RECOMBINATION; FILL-IN; BRCA1; RESECTION; REPAIR; 53BP1; RESISTANCE;

D O I：

10.1016/j.celrep.2018.04.046

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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-STN1TEN1 (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.

引用

页码：2107 / 2118

页数：12

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