Cyclic GMP-AMP Synthase

Genomic DNA can be damaged by endogenous or environmental stresses. During repair, these short single-stranded DNAs are continuously generated and may leak out to the cytoplasm, where they are generally drawn back into the nucleus by DNA repair and replication factors (RPA and Rad51). Alongside this, TREX1, a cytoplasmic exonuclease, is anchored on the outer nuclear membrane to degrade leaking DNAs immediately. This prevents activation of the cGAS/STING pathway against self DNA. Inhibition of any of the above-mentioned proteins leads to accumulation of cytoplasmic DNA and subsequent inflammatory cytokine production.

During interphase, self DNA, existing as nucleosomes, does not trigger cGAS. However, during mitosis, when the nuclear envelope disassembles, there exists a possibility of self-DNA detection by cGAS, leading to the production of type I IFNs. cGAS binds to nucleosomes with a much higher affinity than to naked DNA, using distinct mechanisms in both cases. Nucleosomes also suppress the cGAMP synthase activity of cGAS, hence, not allowing production/activation of downstream molecules. In this stage of mitosis, nucleosomes competitively interfere with cGAS activation.

However, during mitotic arrest, when cGAS is bound for a prolonged time, it gets activated and serves as a signal for error in the cell cycle. It stimulates mitochondrial relocalisation of IRF3, which, in turn, activates Bax-mediated apoptosis. Apart from cGAS, other exogenous DNA sensors are also known – one of them being IFI16 (interferon-g inducible protein 16). IFI16 is shown (in human keratinocytes) to be required for the cGAMP-induced activation of STING, and its interaction with STING promotes STING phosphorylation and translocation. It can be said that these two cytoplasmic DNA sensors cooperate during DNA sensing, and both are required for the full activation of an innate immune response. They also prevent spurious activation of the type I interferon response by adding another level of regulation. DNA binding to cGAS induces the formation of liquid-like droplets, which function as micro reactors in which the enzyme (activated cGAS) and reactants (ATP, GTP) are concentrated to enhance the production of cGAMP. This mechanism allows cGAS to detect the presence of DNA in the cytoplasm only above a certain threshold. Such a switch-like response is made possible by the multivalent interactions between the DNA binding domains of cGAS and DNA, with the mechanism depending on the DNA length as well as on Zn2+ concentration.

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