Publication

BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity

Heijink, A. M., Talens, F., Jae, L. T., van Gijn, S. E., Fehrmann, R. S. N., Brummelkamp, T. R. & van Vugt, M. A. T. M., 9-Jan-2019, In : Nature Communications. 10, 1, 14 p., 100.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Heijink, A. M., Talens, F., Jae, L. T., van Gijn, S. E., Fehrmann, R. S. N., Brummelkamp, T. R., & van Vugt, M. A. T. M. (2019). BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. Nature Communications, 10(1), [100]. https://doi.org/10.1038/s41467-018-07927-y

Author

Heijink, Anne Margriet ; Talens, Francien ; Jae, Lucas T ; van Gijn, Stephanie E ; Fehrmann, Rudolf S N ; Brummelkamp, Thijn R ; van Vugt, Marcel A T M. / BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. In: Nature Communications. 2019 ; Vol. 10, No. 1.

Harvard

Heijink, AM, Talens, F, Jae, LT, van Gijn, SE, Fehrmann, RSN, Brummelkamp, TR & van Vugt, MATM 2019, 'BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity' Nature Communications, vol. 10, no. 1, 100. https://doi.org/10.1038/s41467-018-07927-y

Standard

BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. / Heijink, Anne Margriet; Talens, Francien; Jae, Lucas T; van Gijn, Stephanie E; Fehrmann, Rudolf S N; Brummelkamp, Thijn R; van Vugt, Marcel A T M.

In: Nature Communications, Vol. 10, No. 1, 100, 09.01.2019.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Heijink AM, Talens F, Jae LT, van Gijn SE, Fehrmann RSN, Brummelkamp TR et al. BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. Nature Communications. 2019 Jan 9;10(1). 100. https://doi.org/10.1038/s41467-018-07927-y


BibTeX

@article{b16994ac19f74ec9a4ad5afa59b52de7,
title = "BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity",
abstract = "Loss of BRCA2 affects genome stability and is deleterious for cellular survival. Using a genome-wide genetic screen in near-haploid KBM-7 cells, we show that tumor necrosis factor-alpha (TNF alpha) signaling is a determinant of cell survival upon BRCA2 inactivation. Specifically, inactivation of the TNF receptor (TNFR1) or its downstream effector SAM68 rescues cell death induced by BRCA2 inactivation. BRCA2 inactivation leads to proinflammatory cytokine production, including TNF alpha, and increases sensitivity to TNF alpha. Enhanced TNF alpha sensitivity is not restricted to BRCA2 inactivation, as BRCA1 or FANCD2 inactivation, or hydroxyurea treatment also sensitizes cells to TNF alpha. Mechanistically, BRCA2 inactivation leads to cGAS-positive micronuclei and results in a cell-intrinsic interferon response, as assessed by quantitative mass-spectrometry and gene expression profiling, and requires ASK1 and JNK signaling. Combined, our data reveals that micronuclei induced by loss of BRCA2 instigate a cGAS/STING-mediated interferon response, which encompasses rewired TNF alpha signaling and enhances TNF alpha sensitivity.",
keywords = "NF-KAPPA-B, CANCER SUSCEPTIBILITY GENE, EMBRYONIC CELLULAR PROLIFERATION, SUSTAINED JNK ACTIVATION, DNA-DAMAGE RESPONSE, STRAND BREAK REPAIR, HOMOLOGOUS RECOMBINATION, CHROMOSOMAL INSTABILITY, MICE LACKING, HUMAN-CELLS",
author = "Heijink, {Anne Margriet} and Francien Talens and Jae, {Lucas T} and {van Gijn}, {Stephanie E} and Fehrmann, {Rudolf S N} and Brummelkamp, {Thijn R} and {van Vugt}, {Marcel A T M}",
year = "2019",
month = "1",
day = "9",
doi = "10.1038/s41467-018-07927-y",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity

AU - Heijink, Anne Margriet

AU - Talens, Francien

AU - Jae, Lucas T

AU - van Gijn, Stephanie E

AU - Fehrmann, Rudolf S N

AU - Brummelkamp, Thijn R

AU - van Vugt, Marcel A T M

PY - 2019/1/9

Y1 - 2019/1/9

N2 - Loss of BRCA2 affects genome stability and is deleterious for cellular survival. Using a genome-wide genetic screen in near-haploid KBM-7 cells, we show that tumor necrosis factor-alpha (TNF alpha) signaling is a determinant of cell survival upon BRCA2 inactivation. Specifically, inactivation of the TNF receptor (TNFR1) or its downstream effector SAM68 rescues cell death induced by BRCA2 inactivation. BRCA2 inactivation leads to proinflammatory cytokine production, including TNF alpha, and increases sensitivity to TNF alpha. Enhanced TNF alpha sensitivity is not restricted to BRCA2 inactivation, as BRCA1 or FANCD2 inactivation, or hydroxyurea treatment also sensitizes cells to TNF alpha. Mechanistically, BRCA2 inactivation leads to cGAS-positive micronuclei and results in a cell-intrinsic interferon response, as assessed by quantitative mass-spectrometry and gene expression profiling, and requires ASK1 and JNK signaling. Combined, our data reveals that micronuclei induced by loss of BRCA2 instigate a cGAS/STING-mediated interferon response, which encompasses rewired TNF alpha signaling and enhances TNF alpha sensitivity.

AB - Loss of BRCA2 affects genome stability and is deleterious for cellular survival. Using a genome-wide genetic screen in near-haploid KBM-7 cells, we show that tumor necrosis factor-alpha (TNF alpha) signaling is a determinant of cell survival upon BRCA2 inactivation. Specifically, inactivation of the TNF receptor (TNFR1) or its downstream effector SAM68 rescues cell death induced by BRCA2 inactivation. BRCA2 inactivation leads to proinflammatory cytokine production, including TNF alpha, and increases sensitivity to TNF alpha. Enhanced TNF alpha sensitivity is not restricted to BRCA2 inactivation, as BRCA1 or FANCD2 inactivation, or hydroxyurea treatment also sensitizes cells to TNF alpha. Mechanistically, BRCA2 inactivation leads to cGAS-positive micronuclei and results in a cell-intrinsic interferon response, as assessed by quantitative mass-spectrometry and gene expression profiling, and requires ASK1 and JNK signaling. Combined, our data reveals that micronuclei induced by loss of BRCA2 instigate a cGAS/STING-mediated interferon response, which encompasses rewired TNF alpha signaling and enhances TNF alpha sensitivity.

KW - NF-KAPPA-B

KW - CANCER SUSCEPTIBILITY GENE

KW - EMBRYONIC CELLULAR PROLIFERATION

KW - SUSTAINED JNK ACTIVATION

KW - DNA-DAMAGE RESPONSE

KW - STRAND BREAK REPAIR

KW - HOMOLOGOUS RECOMBINATION

KW - CHROMOSOMAL INSTABILITY

KW - MICE LACKING

KW - HUMAN-CELLS

U2 - 10.1038/s41467-018-07927-y

DO - 10.1038/s41467-018-07927-y

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 100

ER -

ID: 73909118