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DOI | 10.1038/s41467-017-02571-4 |
BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity | |
Heijink, Anne Margriet1; Talens, Francien1; Jae, Lucas T.2,3; van Gijn, Stephanie E.1; Fehrmann, Rudolf S. N.1; Brummelkamp, Thijn R.4,5,6; van Vugt, Marcel A. T. M.1 | |
2019-01-09 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2019 |
卷号 | 10 |
文章类型 | Article |
语种 | 英语 |
国家 | Netherlands; Germany; Austria |
英文摘要 | 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. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000455264100012 |
WOS关键词 | 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 |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203634 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Groningen, Univ Med Ctr Groningen, Canc Res Ctr Groningen, Dept Med Oncol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands; 2.Ludwig Maximilians Univ Munchen, Gene Ctr, Feodor Lynen Str 25, D-81377 Munich, Germany; 3.Ludwig Maximilians Univ Munchen, Dept Biochem, Feodor Lynen Str 25, D-81377 Munich, Germany; 4.Netherlands Canc Inst, Oncode Inst, Div Biochem, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands; 5.Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands; 6.Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria |
推荐引用方式 GB/T 7714 | Heijink, Anne Margriet,Talens, Francien,Jae, Lucas T.,et al. BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity[J]. NATURE COMMUNICATIONS,2019,10. |
APA | Heijink, Anne Margriet.,Talens, Francien.,Jae, Lucas T..,van Gijn, Stephanie E..,Fehrmann, Rudolf S. N..,...&van Vugt, Marcel A. T. M..(2019).BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity.NATURE COMMUNICATIONS,10. |
MLA | Heijink, Anne Margriet,et al."BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity".NATURE COMMUNICATIONS 10(2019). |
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