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

Research output: Contribution to journalJournal articleResearchpeer-review

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BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. / Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Tuckova, Lucie; Jensen, Kamilla E; Maya-Mendoza, Apolinar; Holst, Camilla B.; Mollgaard, Kjeld; Rasmussen, Jane S.; Brennum, Jannick; Bartek, Jiri, Jr.; Syrucek, Martin; Sedlakova, Eva; Andersen, Klaus K.; Frederiksen, Marie H.; Bartek, Jiri; Hamerlik, Petra.

In: Nature Communications, Vol. 7, 13398, 15.11.2016.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Rasmussen, RD, Gajjar, MK, Tuckova, L, Jensen, KE, Maya-Mendoza, A, Holst, CB, Mollgaard, K, Rasmussen, JS, Brennum, J, Bartek, JJ, Syrucek, M, Sedlakova, E, Andersen, KK, Frederiksen, MH, Bartek, J & Hamerlik, P 2016, 'BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity', Nature Communications, vol. 7, 13398. https://doi.org/10.1038/ncomms13398

APA

Rasmussen, R. D., Gajjar, M. K., Tuckova, L., Jensen, K. E., Maya-Mendoza, A., Holst, C. B., ... Hamerlik, P. (2016). BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. Nature Communications, 7, [13398]. https://doi.org/10.1038/ncomms13398

Vancouver

Rasmussen RD, Gajjar MK, Tuckova L, Jensen KE, Maya-Mendoza A, Holst CB et al. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. Nature Communications. 2016 Nov 15;7. 13398. https://doi.org/10.1038/ncomms13398

Author

Rasmussen, Rikke D. ; Gajjar, Madhavsai K. ; Tuckova, Lucie ; Jensen, Kamilla E ; Maya-Mendoza, Apolinar ; Holst, Camilla B. ; Mollgaard, Kjeld ; Rasmussen, Jane S. ; Brennum, Jannick ; Bartek, Jiri, Jr. ; Syrucek, Martin ; Sedlakova, Eva ; Andersen, Klaus K. ; Frederiksen, Marie H. ; Bartek, Jiri ; Hamerlik, Petra. / BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. In: Nature Communications. 2016 ; Vol. 7.

Bibtex

@article{ab29292c36d443e184e379dc067a85d3,
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.",
author = "Rasmussen, {Rikke D.} and Gajjar, {Madhavsai K.} and Lucie Tuckova and Jensen, {Kamilla E} and Apolinar Maya-Mendoza and Holst, {Camilla B.} and Kjeld Mollgaard and Rasmussen, {Jane S.} and Jannick Brennum and Bartek, {Jiri, Jr.} and Martin Syrucek and Eva Sedlakova and Andersen, {Klaus K.} and Frederiksen, {Marie H.} and Jiri Bartek and Petra Hamerlik",
year = "2016",
month = "11",
day = "15",
doi = "10.1038/ncomms13398",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

AU - Rasmussen, Rikke D.

AU - Gajjar, Madhavsai K.

AU - Tuckova, Lucie

AU - Jensen, Kamilla E

AU - Maya-Mendoza, Apolinar

AU - Holst, Camilla B.

AU - Mollgaard, Kjeld

AU - Rasmussen, Jane S.

AU - Brennum, Jannick

AU - Bartek, Jiri, Jr.

AU - Syrucek, Martin

AU - Sedlakova, Eva

AU - Andersen, Klaus K.

AU - Frederiksen, Marie H.

AU - Bartek, Jiri

AU - Hamerlik, Petra

PY - 2016/11/15

Y1 - 2016/11/15

N2 - 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.

AB - 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.

UR - https://www.nature.com/articles/s41467-018-07892-6

U2 - 10.1038/ncomms13398

DO - 10.1038/ncomms13398

M3 - Journal article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13398

ER -

ID: 169943448