Department of Medical Oncology, University Medical Center Groningen, Cancer Research Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands.
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377, Munich, Germany.
Nat Commun. 2019 Jan 9;10(1):100. doi: 10.1038/s41467-018-07927-y.
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 (TNFα) 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 pro-inflammatory cytokine production, including TNFα, and increases sensitivity to TNFα. Enhanced TNFα sensitivity is not restricted to BRCA2 inactivation, as BRCA1 or FANCD2 inactivation, or hydroxyurea treatment also sensitizes cells to TNFα. 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 re-wired TNFα signaling and enhances TNFα sensitivity.
BRCA2 的缺失会影响基因组稳定性，并对细胞存活产生有害影响。我们利用近单倍体 KBM-7 细胞中的全基因组遗传筛选，表明肿瘤坏死因子-α（TNFα）信号是 BRCA2 失活后细胞存活的决定因素。具体来说，TNF 受体（TNFR1）或其下游效应物 SAM68 的失活可挽救 BRCA2 失活诱导的细胞死亡。BRCA2 的缺失会导致促炎细胞因子的产生，包括 TNFα，并增加对 TNFα 的敏感性。增强的 TNFα 敏感性不仅限于 BRCA2 的缺失，因为 BRCA1 或 FANCD2 的缺失或羟基脲处理也会使细胞对 TNFα 敏感。从机制上讲，BRCA2 的缺失会导致 cGAS 阳性的微核，并导致细胞内在的干扰素反应，如定量质谱和基因表达谱分析所示，并且需要 ASK1 和 JNK 信号。综上所述，我们的数据表明，BRCA2 缺失诱导的微核引发了 cGAS/STING 介导的干扰素反应，其中包括重新布线的 TNFα 信号和增强的 TNFα 敏感性。
