cGAS is a pattern-recognition receptor for dsDNA and forms 2cGAS:2DNA dimers followed by oligomerization into phase-separated condensates when fully-complementary DNA is studied. However, many DNAs are not fully complementary. We report that DNA with unpaired regions such as those found during transcription, recombination or replication (designated as bubble-DNA, Bu-DNA) causes cGAS hyper-activation. Hyperactivation is observed by Bu-DNA embedded in linear DNA, circular DNA, plasmid DNA and mitochondria DNA. Bu-DNA binds significantly more tightly to the cGAS catalytic domain than paired-DNA but suppresses condensation. Cryo-EM and single-molecule FRET reveal that cGAS forms 2cGAS:1DNA complexes by bending Bu-DNA into a V-shape using the unpaired region as a hinge, limiting its oligomeric state. This uncovers a novel mode of cGAS activation attributed to pattern diversity within pattern ligands.
Yang, S., Wu, S., Chen, S., Li, X., Chelepis, I., Willcox, S., Barnett, K. C., Hu, X., Huang, G., Brickey, W. J., Duncan, J. A., Chou, W.-C., Liu, P., Fusco, W. G., Torres, S. M., Shadel, G. S., Bowman, G., Griffith, J. D., Sohn, J., Ting, J. P.- Y.
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