BRCA1 - regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023884%3A_____%2F16%3A%230006926" target="_blank" >RIV/00023884:_____/16:#0006926 - isvavai.cz</a>
Alternative codes found
RIV/61989592:15110/16:33160118 RIV/00098892:_____/16:N0000141
Result on the web
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DOI - Digital Object Identifier
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Alternative languages
Result language
angličtina
Original language name
BRCA1 - regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
FP - Other medical fields
OECD FORD branch
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Result continuities
Project
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Continuities
N - Vyzkumna aktivita podporovana z neverejnych zdroju
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Nature communications
ISSN
2041-1723
e-ISSN
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Volume of the periodical
7
Issue of the periodical within the volume
13398
Country of publishing house
GB - UNITED KINGDOM
Number of pages
14
Pages from-to
1-14
UT code for WoS article
000387972000001
EID of the result in the Scopus database
2-s2.0-84995428246