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

Rikke D Rasmussen,Klaus K Andersen,Madhavsai K Gajjar,Apolinar Maya-Mendoza,Camilla B Holst,Martin Syrucek,Marie H Frederiksen,Jiri Bartek,Jannick Brennum,Lucie Tuckova,Jane S Rasmussen,Kamilla E Jensen,Eva Sedlakova,Kjeld Møllgaard,Petra Hamerlik

doi:10.1038/ncomms13398

Rikke D Rasmussen, Klaus K Andersen + Show 13 more

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https://doi.org/10.1038/ncomms13398

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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.

Highlights

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types
Cells are sensitive during S phase when DNA damage causes replication fork stalling or collapse, collectively referred to as replication stress, one of the emerging hallmarks of cancer[40]
To cope with such problems, cells evolved a complex monitoring system called S-phase checkpoint, which becomes activated in response to stalled forks and DNA damage in order to trigger appropriate cellular responses

Summary

Introduction

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. 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. 10 Department of Radiation Biology, Copenhagen University Hospital, Faithful completion of chromosomal DNA replication is essential for genome integrity. Fanconi anaemia and tumour suppressor BRCA1/2 proteins protect the replication forks These proteins stabilize nucleoprotein filaments composed of RAD51 and nascent single stranded DNA (ssDNA) at stalled forks, thereby preventing MRE11 nuclease-mediated DNA strand degradation[2,3]. We identify BRCA1 as a transcriptional regulator of RRM2, a gene encoding the catalytic subunit of ribonucleotide reductase (RNR), which protects GBM cells from endogenous RS and thereby promotes their survival and tumorigenic potential. Triapine alone or in combination with olaparib may represent a novel therapeutic intervention in malignant gliomas

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