Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate immunity (PubMed:23258413, PubMed:24077100, PubMed:25131990, PubMed:23707061, PubMed:23722159, PubMed:29976794, PubMed:30799039, PubMed:21478870, PubMed:23707065, PubMed:24116191, PubMed:24462292, PubMed:32814054, PubMed:33273464, PubMed:26300263, PubMed:33542149, PubMed:31142647). 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] (PubMed:28214358, PubMed:28363908). 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 (PubMed:28314590, PubMed:28363908, PubMed:29976794, PubMed:33230297, PubMed:32817552, PubMed:33606975). Preferentially recognizes and binds curved long dsDNAs of a minimal length of 40 bp (PubMed:30007416). 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 (PubMed:28363908). Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:28363908). Also acts as an innate immune sensor of infection by retroviruses, such as HIV-2, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945, PubMed:24269171, PubMed:30270045, PubMed:32852081). In contrast, HIV-1 is poorly sensed by CGAS, due to its capsid that cloaks viral DNA from CGAS detection (PubMed:24269171, PubMed:30270045, PubMed:32852081). 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 (PubMed:26046437). Also detects the presence of DNA from bacteria, such as M.tuberculosis (PubMed:26048138). 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 (PubMed:24077100). 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 (PubMed:26229115). Also senses the presence of neutrophil extracellular traps (NETs) that are translocated to the cytosol following phagocytosis, leading to synthesis of 2',3'-cGAMP (PubMed:33688080). In addition to foreign DNA, can also be activated by endogenous nuclear or mitochondrial DNA (PubMed:31299200, PubMed:28738408, PubMed:28759889, PubMed:33230297, PubMed:33031745). When self-DNA leaks into the cytosol during cellular stress (such as mitochondrial stress, SARS-CoV-2 infection causing severe COVID-19 disease, DNA damage, mitotic arrest or senescence), or is present in form of cytosolic micronuclei, CGAS is activated leading to a state of sterile inflammation (PubMed:31299200, PubMed:28738408, PubMed:28759889, PubMed:33230297, PubMed:33031745, PubMed:35045565). 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 (By similarity). Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408, PubMed:28759889). Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their 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 (PubMed:28738408, PubMed:28759889). Activated in response to prolonged mitotic arrest, promoting mitotic cell death (PubMed:31299200). 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 (PubMed:31299200, PubMed:33542149). Nuclear CGAS is inactivated by chromatin via direct interaction with nucleosomes, which block CGAS from DNA binding and thus prevent CGAS-induced autoimmunity (PubMed:31299200, PubMed:33542149, PubMed:33051594, PubMed:32911482, PubMed:32912999). 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 (PubMed:30356214, PubMed:31544964). 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 (PubMed:34111399). In contrast to other mammals, human CGAS displays species-specific mechanisms of DNA recognition and produces less 2',3'-cGAMP, allowing a more fine-tuned response to pathogens (PubMed:30007416). ATP + GTP = 2',3'-cGAMP + 2 diphosphate Binds 1 Mg(2+) ion per subunit (PubMed:30007416). Is also active with Mn(2+) (PubMed:32814054). 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 (By similarity). Mn(2+) ions are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues (By similarity). 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 (PubMed:23258413, PubMed:23707061, PubMed:26300263). DNA-binding induces the formation of liquid-like droplets in which CGAS is activated (PubMed:29976794, PubMed:33606975). Liquid-like droplets also create a selective environment that restricts entry of negative regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA (PubMed:33606975). A number of mechanisms exist to restrict its activity toward self-DNA (PubMed:31299200, PubMed:33051594, PubMed:32911482, PubMed:32912999, PubMed:33542149, PubMed:32792394). 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 (PubMed:31299200, PubMed:33051594, PubMed:32911482, PubMed:32912999). CGAS is also inactive when associated with mitotic chromatin (PubMed:33542149). 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 (PubMed:33542149). 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 (PubMed:32792394). DNA-induced activation at micronuclei is also limited by TREX1, which degrades micronuclear DNA upon nuclear envelope rupture, thereby preventing CGAS activation (PubMed:33476576). Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity (PubMed:30799039). Inhibited by aspirin (acetylsalicylate) drug, which acetylates CGAS (PubMed:30799039). Acetylation by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation (PubMed:32817552). Phosphorylation at Ser-305 suppresses the nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at Ser-435 promotes the cyclic GMP-AMP synthase activity (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 inhibits its cyclic GMP-AMP synthase activity (PubMed:33273464). Ubiquitination at Lys-173 and Lys-384 via 'Lys-27'-linked polyubiquitination enhances the cyclic GMP-AMP synthase activity (PubMed:28273161). Monoubiquitination at Lys-347 promotes oligomerization and subsequent activation (PubMed:29426904). Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity (By similarity). The enzyme activity is impaired by the cleavage at Asp-140 and Asp-157 produced by CASP1 (PubMed:28314590). 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 (PubMed:34111399). Strongly inhibited by compound PF-06928215, which is specific for human protein (PubMed:28934246, PubMed:30007416, PubMed:32459092). Inhibited by small-molecule inhibitors with a pyridoindole tricyclic core G108, G140 and G150 (PubMed:31113940). (Microbial infection) Nucleotidyltransferase activity is inhibited by different herpesvirus tegument proteins (Herpes simplex virus 1 tegument protein VP22, herpes virus 8 protein ORF52 and herpesvirus 3 tegument protein VP22/ORF9) (PubMed:34015248, PubMed:34387695). Viral tegument proteins act by disrupting liquid-like droplets in which CGAS is activated, thereby preventing CGAS activity (PubMed:34015248, PubMed:34387695). Monomer in the absence of DNA (PubMed:28363908). Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules (PubMed:33273464, PubMed:30007416, PubMed:30799039, PubMed:31142647). Interacts with nucleosomes; interaction is mainly mediated via histones H2A and H2B and inactivates the nucleotidyltransferase activity by blocking DNA-binding and subsequent activation (PubMed:32911481, PubMed:32911480, PubMed:33051594, PubMed:32911482, PubMed:32912999). Interacts with PQBP1 (via WW domain) (PubMed:26046437). Interacts with TRIM14; this interaction recruits USP14, leading to deubiquitinate and stabilize CGAS and promote type I interferon production (PubMed:27666593, PubMed:32404352). Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS (PubMed:30135424). Interacts with PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex (PubMed:30356214). (Microbial infection) Interacts with herpes virus 8/HHV-8 protein ORF52; this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates CGAS and inhibits its activation. (Microbial infection) Interacts with cytomegalovirus protein UL31; this interaction promotes dissociation of DNA from CGAS, thereby inhibiting the enzymatic activity of CGAS. (Microbial infection) Interacts with herpes simplex virus 1 tegument protein VP22 (UL49); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with herpesvirus 3 tegument protein VP22 (ORF9); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with human cytomegalovirus proteins UL42 and UL83; these interactions result in the inhibition of cGAS-STING signaling. Mainly localizes in the nucleus, and at low level in the cytosol (PubMed:31808743, PubMed:31544964). On chromosomes, enriched on centromeric satellite and LINE DNA repeat elements (PubMed:30811988). Exported from the nucleus to the cytosol in a XPO1/CRM1 via the nuclear export signal in response to DNA stimulation (PubMed:33406424). 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) (PubMed:30827685). Localization at the cell membrane is required to limit the recognition of self-DNA (PubMed:30827685). Following detection of double-stranded DNA (dsDNA), released from the cell membrane into the cytosol in order to signal (PubMed:30827685). Upon transfection with dsDNA forms punctate structures that co-localize with DNA and Beclin-1 (BECN1) (PubMed:26048138). Phosphorylation at Tyr-215 promotes cytosolic retention (PubMed:30356214). In response to translation stress, translocates to the cytosol and associates with collided ribosomes (PubMed:34111399). (Microbial infection) Upon infection with virulent M.tuberculosis forms aggregates with dsDNA, non-virulent bacteria (without the ESX-1 locus) do not form these aggregates (PubMed:26048138). Expressed in the monocytic cell line THP1. By type I interferons. Lys-187 and Leu-195 residues are specific to human and destabilize the interactions with short DNA, shifting the specificity toward the detection of curved long DNAs (PubMed:30007416). Lys-187 and Leu-195 also restrain cGAMP production and, therefore, immune activation, allowing a more fine-tuned response to pathogens (PubMed:30007416). The N-terminal disordered part (1-160) binds unspecifically dsDNA and expands the binding and moving range of CGAS on dsDNA (PubMed:28214358, PubMed:28363908). The disordered and positively charged residues enhance CGAS-DNA phase separation by increasing the valencies of DNA-binding (PubMed:29976794). The N-terminus is required to sense chromatin and its phosphorylation blocks its activation by chromatin DNA (PubMed:33542149). When the N-terminal part (1-160) 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 (1-160) is phosphorylated by AURKB during the G2-M transition, blocking CGAS liquid phase separation and preventing activation (PubMed:33542149). Phosphorylation at Tyr-215 by BLK promotes cytosolic retention (PubMed:30356214). Localizes into the nucleus following dephosphorylation at Tyr-215 (PubMed:30356214). Phosphorylation at Ser-435 activates the nucleotidyltransferase activity (PubMed:32474700). Dephosphorylation at Ser-435 by PPP6C impairs its ability to bind GTP, thereby inactivating it (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 by PRKDC inhibits its cyclic GMP-AMP synthase activity by impairing homodimerization and activation (PubMed:33273464). Phosphorylation at Ser-305 by AKT (AKT1, AKT2 or AKT3) suppresses the nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at Ser-305 by CDK1 during mitosis leads to its inhibition, thereby preventing CGAS activation by self-DNA during mitosis (PubMed:32351706). Dephosphorylated at Ser-305 by protein phosphatase PP1 upon mitotic exit (PubMed:32351706). Ubiquitinated at Lys-414 via 'Lys-48'-linked polyubiquitin chains, leading to its SQSTM1-mediated autophagic degradation (PubMed:27666593). Interaction with TRIM14 promotes recruitment of USP14, leading to deubiquitinate Lys-414 and stabilize CGAS (PubMed:27666593). Ubiquitinated at Lys-173 and Lys-384 by RNF185 via 'Lys-27'-linked polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity (PubMed:28273161). Monoubiquitination at Lys-347 by TRIM56 promotes oligomerization and subsequent activation (PubMed:29426904). Monoubiquitination by TRIM41 promotes CGAS activation (PubMed:29760876). Ubiquitination at Lys-285 and Lys-479 via 'Lys-48'-linked polyubiquitination promotes its degradation (By similarity). Deubiquitination at Lys-285 by USP29 promotes its stabilization (By similarity). Deubiquitinated by USP27X, promoting its stabilization (PubMed:31534008). Sumoylated at Lys-231 and Lys-479 by TRIM38 in uninfected cells and during the early phase of viral infection, promoting its stability by preventing ubiquitination at Lys-285 and Lys-479, and subsequent degradation (By similarity). Desumoylated by SENP2 during the late phase of viral infection (By similarity). Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity (By similarity). Desumoylation at Lys-347, Lys-384 and Lys-394 by SENP7 relieves inhibition and activates CGAS (By similarity). Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6. Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity (PubMed:30799039). Deacetylated upon cytosolic DNA challenge such as viral infections (PubMed:30799039). Acetylation can be mediated by aspirin (acetylsalicylate) drug, which directly acetylates CGAS (PubMed:30799039). Acetylation by aspirin efficiently inhibits CGAS-mediated immune responses and is able to suppress self-DNA-induced autoimmunity (PubMed:30799039). Acetylation at Lys-47, Lys-56, Lys-62 and Lys-83 by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation (PubMed:32817552). Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation (PubMed:30878284). 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 (By similarity). Cleaved by CASP3 at Asp-319 during virus-induced apoptosis, thereby inactivating it and preventing cytokine overproduction (PubMed:30878284). Cleaved by CASP1 at Asp-140 and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 and CASP5 during non-canonical inflammasome activation; they don't cut at the same sites than CASP1 (PubMed:28314590). (Microbial infection) Deamidated on 'Asn-210' by herpes simplex virus 1 protein UL37. This modification significantly reduces CGAS-dependent cGAMP production and innate immune signaling induced by dsDNA. (Microbial infection) Degraded by an autophagy-mediated mechanism in presence of Chikungunya virus capsid protein. The cGAS-STING signaling pathway drives sterile inflammation leading to type I interferon immunopathology in severe COVID-19 disease caused by SARS-CoV-2 virus infection (PubMed:35045565). Tissue damages in the lung and skin lesions are caused by activation of the cGAS-STING signaling leading to aberrant inflammation (PubMed:35045565). Endothelial cell damage is also caused by activation of the cGAS-STING pathway: SARS-CoV-2 infection triggers mitochondrial DNA release into the cytosol (PubMed:35045565). Released mitochondrial DNA is then detected by CGAS, leading to activation of the cGAS-STING pathway, triggering type-I interferon production and autoinflammation (PubMed:35045565). Belongs to the mab-21 family. Extended N-terminus.