DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance

Lina Wang, Siru Li, Kai Wang, Na Wang, Qiaoling Liu, Zhen Sun, Li Wang, Lulu Wang, Quentin Liu, Chengli Song (), Caigang Liu () and Qingkai Yang ()
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Lina Wang: Dalian Medical University
Siru Li: Dalian Medical University
Kai Wang: Dalian Medical University
Na Wang: Dalian Medical University
Qiaoling Liu: Dalian Medical University
Zhen Sun: Dalian Medical University
Li Wang: Chinese Academy of Sciences
Lulu Wang: Dalian University of Technology
Quentin Liu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Chengli Song: Dalian Medical University
Caigang Liu: Shengjing Hospital of China Medical University
Qingkai Yang: Dalian Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34858-6

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