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BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity
RD. Rasmussen, MK. Gajjar, L. Tuckova, KE. Jensen, A. Maya-Mendoza, CB. Holst, K. Møllgaard, JS. Rasmussen, J. Brennum, J. Bartek, M. Syrucek, E. Sedlakova, KK. Andersen, MH. Frederiksen, J. Bartek, P. Hamerlik,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
Nature Open Access
od 2010-12-01
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2010-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
Springer Nature OA/Free Journals
od 2010-12-01
PubMed
27845331
DOI
10.1038/ncomms13398
Knihovny.cz E-zdroje
- MeSH
- analýza přežití MeSH
- glioblastom genetika metabolismus patologie MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádorové buňky kultivované MeSH
- nádory mozku genetika metabolismus patologie MeSH
- protein BRCA1 genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- replikace DNA genetika MeSH
- retrospektivní studie MeSH
- ribonukleosiddifosfátreduktasa genetika metabolismus MeSH
- RNA interference MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
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
Citace poskytuje Crossref.org
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