基因组不稳定性由于失去DNA修复因子会导致发育缺陷、自身炎症性疾病和癌症。两条主要的信号通路被基因组不稳定性激活——DNA损伤检查点信号传导，导致p53激活，和先天免疫，主要由DNA传感器cGAS驱动。与p53一样，cGAS被认为在基因毒性应激中驱动细胞死亡和老化，除了它的经典炎症功能，但其在细胞分化和癌变过程中的作用尚不明确。此外，关于cGAS通路主要具有抑制肿瘤或致癌功能的论点仍存在争议。《癌症研究》杂志本期的一项研究利用血液系统特异性敲除核糖核酸修复基因Rnaseh2b引入基因毒性应激，导致严重的造血系统缺陷和增加血液肿瘤发生率。这两个效应分别由p53所驱动和对抗。令人惊讶的是，尽管存在增强的先天免疫信号传导，但cGAS通路似乎在这两个过程中并不起作用。这些发现表明基因毒性应激对先天免疫反应可能比所认识的更微妙和具有特定背景，这表明需要更详细地了解通路激活和信号后果。请参阅Dressel等人的相关文章，第2858页。© 2023年美国癌症研究协会。

Genome instability due to the loss of DNA repair factors can drive developmental defects, autoinflammatory disease, and cancer. Two major signaling pathways are activated by genome instability-DNA damage checkpoint signaling, leading to p53 activation, and innate immunity, largely driven by the DNA sensor cGAS. Like p53, cGAS is thought to drive cell death and senescence during genotoxic stress in addition to its canonical inflammatory functions, but its role during cellular differentiation and carcinogenesis is poorly understood. Furthermore, it is heavily debated whether the cGAS pathway primarily has tumor-suppressive or oncogenic functions. A study in this issue of Cancer Research used a hematopoietic lineage-specific knockout of the ribonucleotide repair gene Rnaseh2b to introduce genotoxic stress, resulting in severe hematopoiesis defects and increased incidence of hematologic cancers. These two effects were driven by and antagonized by p53, respectively. Surprisingly, despite increased innate immune signaling, the cGAS pathway did not seem to play a role in either process. These findings suggest that innate immune responses to genotoxic stress may be more subtle and context-specific than appreciated, indicating that a more detailed understanding of pathway activation and signaling consequences is needed. See related article by Dressel et al., p. 2858.©2023 American Association for Cancer Research.