Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate immunity. Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p]. Acts as a key DNA sensor: directly binds double-stranded DNA (dsDNA), inducing the formation of liquid-like droplets in which CGAS is activated, leading to synthesis of 2',3'-cGAMP, a second messenger that binds to and activates STING1, thereby triggering type-I interferon production. Preferentially binds long dsDNA (around 45 bp) and forms ladder-like networks that function cooperatively to stabilize individual cGAS-dsDNA complexes. Acts as a key foreign DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses. Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm. Also acts as an innate immune sensor of infection by retroviruses by detecting the presence of reverse-transcribed DNA in the cytosol (By similarity). Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA. Also detects the presence of DNA from bacteria (By similarity). 2',3'-cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote STING1 activation and convey immune response to connecting cells. 2',3'-cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN-induction in newly infected cells in a cGAS-independent but STING1-dependent manner. Also senses the presence of neutrophil extracellular traps (NETs) that are translocated to the cytosol following phagocytosis, leading to synthesis of 2',3'-cGAMP (By similarity). In addition to foreign DNA, can also be activated by endogenous nuclear or mitochondrial DNA (By similarity). When self-DNA leaks into the cytosol during cellular stress (such as mitochondrial stress, DNA damage, mitotic arrest or senescence), or is present in form of cytosolic micronuclei, CGAS is activated leading to a state of sterile inflammation. Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via STING1 and promote cellular senescence. Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability. Micronuclei, which as frequently found in cancer cells, consist of chromatin surrounded by its own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to 2',3'-cGAMP synthesis and subsequent activation of STING1 and type-I interferon production (By similarity). In a healthy cell, CGAS is however kept inactive even in cellular events that directly expose it to self-DNA, such as mitosis, when cGAS associates with chromatin directly after nuclear envelope breakdown or remains in the form of postmitotic persistent nuclear cGAS pools bound to chromatin (By similarity). Nuclear CGAS is inactivated by chromatin via direct interaction with nucleosomes, which block CGAS from DNA binding and thus prevent CGAS-induced autoimmunity. Also acts as a suppressor of DNA repair in response to DNA damage: inhibits homologous recombination repair by interacting with PARP1, the CGAS-PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex (By similarity). In addition to DNA, also sense translation stress: in response to translation stress, translocates to the cytosol and associates with collided ribosomes, promoting its activation and triggering type-I interferon production (By similarity). ATP + GTP = 2',3'-cGAMP + 2 diphosphate Binds 1 Mg(2+) per subunit. Is also active with Mn(2+). Mn(2+)-activated enyzme forms an inverted pppGp(2'-5')A intermediate, suggesting a non-canonical but accelerated 2',3'-cGAMP cyclization without substrate flip-over. Mn(2+) ions are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc. The enzyme activity is strongly increased by double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA. DNA-binding induces the formation of liquid-like droplets in which CGAS is activated. Liquid-like droplets also create a selective environment that restricts entry of negative regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA (By similarity). A number of mechanisms exist to restrict its activity toward self-DNA. The nucleotidyltransferase activity is inhibited in the nucleus via its association with nucleosomes: interacts with the acidic patch of histones H2A and H2B, thereby blocking DNA-binding and subsequent activation (By similarity). CGAS is also inactive when associated with mitotic chromatin (By similarity). Chromatin-bound CGAS cannot be activated by exogenous DNA in mitotic cells: phosphorylation of the N-terminal disordered part by AURKB during the G2-M transition blocks CGAS liquid phase separation and activation (By similarity). Activity toward self-DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby preventing CGAS activation (By similarity). DNA-induced activation at micronuclei is also limited by TREX1, which degrades micronuclear DNA upon nuclear envelope rupture, thereby preventing CGAS activation. Acetylation at Lys-375, Lys-385 and Lys-405 inhibits the cyclic GMP-AMP synthase activity. Acetylation by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation (By similarity). Phosphorylation at Ser-294 suppresses the nucleotidyltransferase activity. Phosphorylation at Ser-426 promotes the cyclic GMP-AMP synthase activity (By similarity). Phosphorylation at Ser-202 inhibits its cyclic GMP-AMP synthase activity. Ubiquitination at Lys-375 via 'Lys-27'-linked polyubiquitination enhances the cyclic GMP-AMP synthase activity (By similarity). Monoubiquitination at Lys-338 promotes oligomerization and subsequent activation. Sumoylation at Lys-338, Lys-375 and Lys-385 prevents DNA-binding, oligomerization and nucleotidyltransferase activity. The enzyme activity is impaired by the cleavage by CASP1 (By similarity). In addition to DNA, also activated by collided ribosomes upon translation stress: specifically binds collided ribosomes, promoting its activation and triggering type-I interferon production (By similarity). Monomer in the absence of DNA. Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules. Interacts with nucleosomes; interaction is mainly mediated via histones H2A and H2B and inactivates the nucleotidyltransferase activity by blocking DNA-binding and subsequent activation (By similarity). Interacts with PQBP1 (via WW domain). Interacts with TRIM14; this interaction recruits USP14, leading to deubiquitinate and stabilize CGAS and promote type I interferon production. Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS. Interacts with PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex (By similarity). Mainly localizes in the nucleus, and at low level in the cytosol (By similarity). On chromosomes, enriched on centromeric satellite and LINE DNA repeat elements. Exported from the nucleus to the cytosol in a XPO1/CRM1 via the nuclear export signal in response to DNA stimulation (By similarity). Outside the nucleus, localizes at the cell membrane as a peripheral membrane protein in resting conditions: association to the cell membrane is mediated via binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (By similarity). Localization at the cell membrane is required to limit the recognition of self-DNA. Following detection of double-stranded DNA (dsDNA), released from the cell membrane into the cytosol in order to signal. Upon transfection with dsDNA forms punctate structures that co-localize with DNA and Beclin-1 (BECN1). Phosphorylation at Tyr-204 promotes cytosolic retention. In response to translation stress, translocates to the cytosol and associates with collided ribosomes (By similarity). The N-terminal disordered part (1-148) binds unspecifically dsDNA and expands the binding and moving range of CGAS on dsDNA (By similarity). The disordered and positively charged residues enhance CGAS-DNA phase separation by increasing the valencies of DNA-binding. The N-terminus is required to sense chromatin and its phosphorylation blocks its activation by chromatin DNA (By similarity). When the N-terminal part (1-148) is missing the protein bound to dsDNA homodimerizes (By similarity). The arginine-anchor tightly binds to the canonical H2A acidic-patch residues. The N-terminal disordered part (1-146) is phosphorylated by AURKB during the G2-M transition, blocking CGAS liquid phase separation and preventing activation. Phosphorylation at Tyr-204 by BLK promotes cytosolic retention. Localizes into the nucleus following dephosphorylation at Tyr-204 (By similarity). Phosphorylation at Ser-426 activates the nucleotidyltransferase activity. Dephosphorylation at Ser-426 by PPP6C impairs its ability to bind GTP, thereby inactivating it (By similarity). Phosphorylation at Ser-202 by PRKDC inhibits its cyclic GMP-AMP synthase activity by impairing homodimerization and activation (By similarity). Phosphorylation at Ser-294 by AKT (AKT1, AKT2 or AKT3) suppresses the nucleotidyltransferase activity. Phosphorylation at Ser-294 by CDK1 during mitosis leads to its inhibition, thereby preventing CGAS activation by self-DNA during mitosis. Dephosphorylated at Ser-294 by protein phosphatase PP1 upon mitotic exit (By similarity). Ubiquitinated at Lys-405 via 'Lys-48'-linked polyubiquitin chains, leading to its SQSTM1-mediated autophagic degradation. Interaction with TRIM14 promotes recruitment of USP14, leading to deubiquitinate Lys-405 and stabilize CGAS. Ubiquitinated at Lys-375 by RNF185 via 'Lys-27'-linked polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity (By similarity). Monoubiquitination at Lys-338 by TRIM56 promotes oligomerization and subsequent activation (By similarity). Monoubiquitination by TRIM41 promotes CGAS activation (By similarity). Ubiquitination at Lys-274 via 'Lys-48'-linked polyubiquitination promotes its degradation. Deubiquitination at Lys-274 by USP29 promotes its stabilization. Deubiquitinated by USP27X, promoting its stabilization (By similarity). Sumoylated by TRIM38 in uninfected cells and during the early phase of viral infection, promoting its stability by preventing ubiquitination at Lys-274, and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection. Sumoylation at Lys-338, Lys-375 and Lys-385 prevents DNA-binding, oligomerization and nucleotidyltransferase activity. Desumoylation at Lys-338, Lys-375 and Lys-385 by SENP7 relieves inhibition and activates CGAS. Polyglutamylated by TTLL6 at Glu-275, leading to impair DNA-binding activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6. Acetylation at Lys-375, Lys-385 and Lys-405 inhibits the cyclic GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge such as viral infections. Acetylation by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation. Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation. The damage of the nucleus and the mitochondria during apoptosis leads to leakage of nuclear and mitochondrial DNA, which activate CGAS: cleavage and inactivation during apoptosis in required to prevent cytokine overproduction. Cleaved by CASP7 and CASP3 during virus-induced apoptosis, thereby inactivating it and preventing cytokine overproduction. Cleaved by CASP1 upon DNA virus infection; the cleavage impairs cGAMP production. Also cleaved by the pyroptotic CASP4 during non-canonical inflammasome activation; does not cut at the same sites than CASP1. Belongs to the mab-21 family.