Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
EMBO J. 2020 Jul 15;39(14):e104036. doi: 10.15252/embj.2019104036. Epub 2020 Jun 2.
Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation-induced innate immune responses. Using a series of mammalian knockout cell lines, we demonstrate that, surprisingly, both the cGAS/STING-dependent DNA-sensing pathway and the MAVS-dependent RNA-sensing pathway are responsible for type I interferon signaling induced by ionizing radiation in the presence or absence of ATR inhibitors. The relative contributions of these two pathways in type I interferon signaling depend on cell type and/or genetic background. We propose that DNA damage-elicited double-strand DNA breaks releases DNA fragments, which may either activate the cGAS/STING-dependent pathway or-especially in the case of AT-rich DNA sequences-be transcribed and initiate MAVS-dependent RNA sensing and signaling. Together, our results suggest the involvement of two distinct pathways in type I interferon signaling upon DNA damage. Moreover, radiation plus ATR inhibition may be a promising new combination therapy against cancer.
深入了解电离辐射如何诱导 I 型干扰素信号转导，以及如何放大这一信号模块，应有助于最大限度地提高放射疗法的疗效。在本研究中，我们报告称，ATR （ataxia-telangiectasia and Rad3-related protein kinase）的 DNA 损伤反应激酶抑制剂可显著增强电离辐射诱导的固有免疫反应。通过一系列哺乳动物敲除细胞系，我们证明令人惊讶的是，在存在或不存在 ATR 抑制剂的情况下，cGAS/STING 依赖性 DNA 感应途径和 MAVS 依赖性 RNA 感应途径均负责由电离辐射诱导的 I 型干扰素信号转导。这两种途径在 I 型干扰素信号转导中的相对贡献取决于细胞类型和/或遗传背景。我们提出，DNA 损伤引发的双链 DNA 断裂会释放 DNA 片段，这些片段可能激活 cGAS/STING 依赖性途径，或者——特别是在富含 AT 的 DNA 序列的情况下——被转录并启动 MAVS 依赖性 RNA 感应和信号转导。总之，我们的研究结果表明，在 DNA 损伤后，I 型干扰素信号转导涉及两种不同的途径。此外，放射治疗联合 ATR 抑制可能是一种针对癌症的很有前途的新联合治疗方法。
