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Cell Cycle Checkpoints Cooperate to Suppress DNA- and RNA-Associated Molecular Pattern Recognition and Anti-Tumor Immune Responses.
Cell Reports ( IF 7.5 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.celrep.2020.108080
Jie Chen 1 , Shane M Harding 1 , Ramakrishnan Natesan 1 , Lei Tian 1 , Joseph L Benci 2 , Weihua Li 1 , Andy J Minn 2 , Irfan A Asangani 3 , Roger A Greenberg 1
Affiliation  

The DNA-dependent pattern recognition receptor, cGAS (cyclic GMP-AMP synthase), mediates communication between the DNA damage and the immune responses. Mitotic chromosome missegregation stimulates cGAS activity; however, it is unclear whether progression through mitosis is required for cancercell-intrinsic activation of anti-tumor immune responses. Moreover, it is unknown whether cell cycle checkpoint disruption can restore responses in cancer cells that are recalcitrant to DNAdamage-induced inflammation. Here, we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either excessive DNA damage or CDK1 inhibition prevents inflammatory-stimulated gene expression and immune-mediated destruction of distal tumors. Remarkably, DNAdamage-induced inflammatory signaling is restored in a RIG-I-dependent manner upon concomitant disruption of p53 and the G2 checkpoint. These findings link aberrant cell progression and p53 loss to an expanded spectrum of damage-associated molecular pattern recognition and have implications for the design of rational approaches to augment anti-tumor immune responses.



中文翻译:

细胞周期检查点合作抑制DNA和RNA相关的分子模式识别和抗肿瘤免疫反应。

DNA依赖性模式识别受体cGAS(环状GMP-AMP合酶)介导DNA损伤与免疫反应之间的通讯。有丝分裂染色体错聚刺激cGAS活性。然而,目前尚不清楚通过癌细胞的本征激活抗肿瘤免疫反应是否需要通过有丝分裂进行。此外,尚不清楚细胞周期检查点的破坏能否恢复对DNA损伤诱导的炎症有害的癌细胞的反应。在这里,我们证明了延长的细胞周期停滞在G 2DNA过度损伤或CDK1抑制引起的有丝分裂边界可防止炎症刺激的基因表达和远端肿瘤的免疫介导破坏。值得注意的是,伴随p53和G 2检查点的破坏,DNA损伤诱导的炎症信号以RIG-I依赖性方式得以恢复。这些发现将异常的细胞进程和p53丢失与损伤相关分子模式识别的广泛范围联系起来,并且对设计合理的方法以增强抗肿瘤免疫应答具有影响。

更新日期:2020-09-01
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