Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.

Brain Tumor Biology Danish Cancer Society Research Center Strandboulevarden 49 Copenhagen DK 2100 Denmark

Department of Cellular and Molecular Medicine Faculty of Health and Medical Sciences University of Copenhagen Blegdamsvej 3 Copenhagen 2200 DK Denmark

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Hnevotinska 3 Olomouc 77515 Czech Republic

Department of Medicine Unit of Microbial Pathogenesis Karolinska Institutet and Department of Neurosurgery Karolinska University Hospital Solna 171 76 Stockholm Sweden

Department of Neurosurgery Copenhagen University Hospital Blegdamsvej 9 Copenhagen DK 2100 Denmark

Department of Pathology Hospital Na Homolce Roentgenova 2 150 30 Praha 5 Czech Republic

Department of Radiation Biology Copenhagen University Hospital Blegdamsvej 9 Copenhagen 2100 DK Denmark

Division of Translational Medicine and Chemical Biology Department of Medical Biochemistry and Biophysics Science for Life Laboratory Karolinska Institute Scheeles vag 2 Stockholm 17177 Sweden

Genome Integrity Unit Danish Cancer Society Research Center Strandboulevarden 49 Copenhagen DK 2100 Denmark

Statistics Bioinformatics and Registry Unit Danish Cancer Society Research Center Strandboulevarden 49 Copenhagen DK 2100 Denmark

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Nat Commun. 2018 Dec 19;9(1):5396. doi: 10.1038/s41467-018-07892-6. PubMed

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