DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance
- Nat Commun. 2022 Nov 19;13(1):7107. doi: 10.1038/s41467-022-34858-6.
- 1. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
- 2. CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
- 3. School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
- 4. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
- 5. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China. [email protected].
- 6. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China. [email protected].
- 7. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China. [email protected].
- # Contributed equally.
DNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of Cyclic GMP-AMP Synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.