title: BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity.
abstract: 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.
authors.affiliation: Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Rikke D
authors.initials: RD
authors.lastname: Rasmussen
authors.affiliation: Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Madhavsai K
authors.initials: MK
authors.lastname: Gajjar
authors.affiliation: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Tuckova
authors.affiliation: Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Kamilla E
authors.initials: KE
authors.lastname: Jensen
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Apolinar
authors.initials: A
authors.lastname: Maya-Mendoza
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200-DK, Denmark.
authors.forename: Camilla B
authors.identifier: 0000-0002-6225-3551
authors.initials: CB
authors.lastname: Holst
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200-DK, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Møllgaard
authors.affiliation: Department of Neurosurgery, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen DK-2100, Denmark.
authors.forename: Jane S
authors.initials: JS
authors.lastname: Rasmussen
authors.affiliation: Department of Neurosurgery, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen DK-2100, Denmark.
authors.forename: Jannick
authors.initials: J
authors.lastname: Brennum
authors.affiliation: Department of Neurosurgery, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen DK-2100, Denmark.|Department of Medicine, Unit of Microbial Pathogenesis, Karolinska Institutet and Department of Neurosurgery, Karolinska University Hospital, Solna 171 76, Stockholm, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Department of Pathology, Hospital Na Homolce, Roentgenova 2, 150 30 Praha 5, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Syrucek
authors.affiliation: Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Sedlakova
authors.affiliation: Statistics, Bioinformatics and Registry Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Andersen
authors.affiliation: Statistics, Bioinformatics and Registry Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: Marie H
authors.initials: MH
authors.lastname: Frederiksen
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, 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.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.|Department of Radiation Biology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100-DK, Denmark.
authors.forename: Petra
authors.initials: P
authors.lastname: Hamerlik
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase