BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Rikke D. Rasmussen, Madhavsai K. Gajjar, Lucie Tuckova, Kamilla E. Jensen, Apolinar Maya-Mendoza, Camilla B. Holst, Kjeld Møllgaard, Jane S. Rasmussen, Jannick Brennum, Jiri Bartek, Martin Syrucek, Eva Sedlakova, Klaus K. Andersen, Marie H. Frederiksen, Jiri Bartek and Petra Hamerlik ()
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Rikke D. Rasmussen: Brain Tumor Biology, Danish Cancer Society Research Center
Madhavsai K. Gajjar: Brain Tumor Biology, Danish Cancer Society Research Center
Lucie Tuckova: Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc
Kamilla E. Jensen: Brain Tumor Biology, Danish Cancer Society Research Center
Apolinar Maya-Mendoza: Genome Integrity Unit, Danish Cancer Society Research Center
Camilla B. Holst: Faculty of Health and Medical Sciences, University of Copenhagen
Kjeld Møllgaard: Faculty of Health and Medical Sciences, University of Copenhagen
Jane S. Rasmussen: Copenhagen University Hospital
Jannick Brennum: Copenhagen University Hospital
Jiri Bartek: Copenhagen University Hospital
Martin Syrucek: Hospital Na Homolce
Eva Sedlakova: Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc
Klaus K. Andersen: Statistics, Bioinformatics and Registry Unit, Danish Cancer Society Research Center
Marie H. Frederiksen: Statistics, Bioinformatics and Registry Unit, Danish Cancer Society Research Center
Jiri Bartek: Genome Integrity Unit, Danish Cancer Society Research Center
Petra Hamerlik: Brain Tumor Biology, Danish Cancer Society Research Center

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13398

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