ID CGAS_MOUSE Reviewed; 507 AA. AC Q8C6L5; Q3ULW3; DT 06-MAR-2013, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 27-MAR-2024, entry version 142. DE RecName: Full=Cyclic GMP-AMP synthase {ECO:0000303|PubMed:23258413}; DE Short=cGAMP synthase {ECO:0000303|PubMed:23258413}; DE Short=cGAS {ECO:0000303|PubMed:23258413}; DE Short=m-cGAS {ECO:0000303|PubMed:23258413}; DE EC=2.7.7.86 {ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416}; DE AltName: Full=2'3'-cGAMP synthase {ECO:0000303|PubMed:23258413}; DE AltName: Full=Mab-21 domain-containing protein 1 {ECO:0000305}; GN Name=Cgas {ECO:0000303|PubMed:23258413, ECO:0000312|MGI:MGI:2442261}; GN Synonyms=Mb21d1 {ECO:0000312|MGI:MGI:2442261}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DNA-BINDING, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF GLU-211 AND ASP-213. RX PubMed=23258413; DOI=10.1126/science.1232458; RA Sun L., Wu J., Du F., Chen X., Chen Z.J.; RT "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type RT I interferon pathway."; RL Science 339:786-791(2013). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Mammary gland, and Ovary; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Limb; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION. RX PubMed=23722158; DOI=10.1038/nature12306; RA Ablasser A., Goldeck M., Cavlar T., Deimling T., Witte G., Rohl I., RA Hopfner K.P., Ludwig J., Hornung V.; RT "cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that RT activates STING."; RL Nature 498:380-384(2013). RN [7] RP FUNCTION. RX PubMed=24077100; DOI=10.1038/nature12640; RA Ablasser A., Schmid-Burgk J.L., Hemmerling I., Horvath G.L., Schmidt T., RA Latz E., Hornung V.; RT "Cell intrinsic immunity spreads to bystander cells via the intercellular RT transfer of cGAMP."; RL Nature 503:530-534(2013). RN [8] RP FUNCTION. RX PubMed=23929945; DOI=10.1126/science.1240933; RA Gao D., Wu J., Wu Y.T., Du F., Aroh C., Yan N., Sun L., Chen Z.J.; RT "Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other RT retroviruses."; RL Science 341:903-906(2013). RN [9] RP PROTEOLYTIC CLEAVAGE. RX PubMed=25525874; DOI=10.1016/j.cell.2014.11.036; RA White M.J., McArthur K., Metcalf D., Lane R.M., Cambier J.C., Herold M.J., RA van Delft M.F., Bedoui S., Lessene G., Ritchie M.E., Huang D.C., Kile B.T.; RT "Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN RT production."; RL Cell 159:1549-1562(2014). RN [10] RP PHOSPHORYLATION AT SER-291, ACTIVITY REGULATION, AND MUTAGENESIS OF RP SER-291. RX PubMed=26440888; DOI=10.1016/j.celrep.2015.09.007; RA Seo G.J., Yang A., Tan B., Kim S., Liang Q., Choi Y., Yuan W., Feng P., RA Park H.S., Jung J.U.; RT "Akt kinase-mediated checkpoint of cGAS DNA sensing pathway."; RL Cell Rep. 13:440-449(2015). RN [11] RP FUNCTION, AND MUTAGENESIS OF GLY-198 AND SER-199. RX PubMed=26229117; DOI=10.1126/science.aab3632; RA Bridgeman A., Maelfait J., Davenne T., Partridge T., Peng Y., Mayer A., RA Dong T., Kaever V., Borrow P., Rehwinkel J.; RT "Viruses transfer the antiviral second messenger cGAMP between cells."; RL Science 349:1228-1232(2015). RN [12] RP SUMOYLATION AT LYS-217 AND LYS-464, UBIQUITINATION AT LYS-271 AND LYS-464, RP AND MUTAGENESIS OF LYS-217; LYS-271; LYS-335 AND LYS-464. RX PubMed=27637147; DOI=10.1016/j.immuni.2016.08.014; RA Hu M.M., Yang Q., Xie X.Q., Liao C.Y., Lin H., Liu T.T., Yin L., Shu H.B.; RT "Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor RT STING to regulate the kinetics of response to DNA virus."; RL Immunity 45:555-569(2016). RN [13] RP GLUTAMYLATION AT GLU-272, GLUTAMYLATION AT GLU-302, AND MUTAGENESIS OF RP GLU-272 AND GLU-302. RX PubMed=26829768; DOI=10.1038/ni.3356; RA Xia P., Ye B., Wang S., Zhu X., Du Y., Xiong Z., Tian Y., Fan Z.; RT "Glutamylation of the DNA sensor cGAS regulates its binding and synthase RT activity in antiviral immunity."; RL Nat. Immunol. 17:369-378(2016). RN [14] RP FUNCTION, DOMAIN, MONOMER, AND DNA-BINDING. RX PubMed=28214358; DOI=10.1002/1873-3468.12598; RA Lee A., Park E.B., Lee J., Choi B.S., Kang S.J.; RT "The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the RT DNA size restriction of core-cGAS activity."; RL FEBS Lett. 591:954-961(2017). RN [15] RP FUNCTION, DOMAIN, CLEAVAGE, AND ACTIVITY REGULATION. RX PubMed=28314590; DOI=10.1016/j.immuni.2017.02.011; RA Wang Y., Ning X., Gao P., Wu S., Sha M., Lv M., Zhou X., Gao J., Fang R., RA Meng G., Su X., Jiang Z.; RT "Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to RT regulate responses to DNA virus infection."; RL Immunity 46:393-404(2017). RN [16] RP FUNCTION, DNA-BINDING, AND DOMAIN. RX PubMed=28363908; DOI=10.4049/jimmunol.1601909; RA Tao J., Zhang X.W., Jin J., Du X.X., Lian T., Yang J., Zhou X., Jiang Z., RA Su X.D.; RT "Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation."; RL J. Immunol. 198:3627-3636(2017). RN [17] RP FUNCTION. RX PubMed=28738408; DOI=10.1038/nature23449; RA Mackenzie K.J., Carroll P., Martin C.A., Murina O., Fluteau A., RA Simpson D.J., Olova N., Sutcliffe H., Rainger J.K., Leitch A., Osborn R.T., RA Wheeler A.P., Nowotny M., Gilbert N., Chandra T., Reijns M.A.M., RA Jackson A.P.; RT "cGAS surveillance of micronuclei links genome instability to innate RT immunity."; RL Nature 548:461-465(2017). RN [18] RP FUNCTION. RX PubMed=28759028; DOI=10.1038/ncb3586; RA Glueck S., Guey B., Gulen M.F., Wolter K., Kang T.W., Schmacke N.A., RA Bridgeman A., Rehwinkel J., Zender L., Ablasser A.; RT "Innate immune sensing of cytosolic chromatin fragments through cGAS RT promotes senescence."; RL Nat. Cell Biol. 19:1061-1070(2017). RN [19] RP SUMOYLATION AT LYS-335; LYS-372 AND LYS-382, DESUMOYLATION BY SENP7, RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-335; LYS-372 AND RP LYS-382. RX PubMed=28095500; DOI=10.1371/journal.ppat.1006156; RA Cui Y., Yu H., Zheng X., Peng R., Wang Q., Zhou Y., Wang R., Wang J., RA Qu B., Shen N., Guo Q., Liu X., Wang C.; RT "SENP7 potentiates cGAS activation by relieving SUMO-mediated inhibition of RT cytosolic DNA sensing."; RL PLoS Pathog. 13:e1006156-e1006156(2017). RN [20] RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF ASN-172; RP ARG-180; CYS-419 AND HIS-467. RX PubMed=30007416; DOI=10.1016/j.cell.2018.06.026; RA Zhou W., Whiteley A.T., de Oliveira Mann C.C., Morehouse B.R., Nowak R.P., RA Fischer E.S., Gray N.S., Mekalanos J.J., Kranzusch P.J.; RT "Structure of the human cGAS-DNA complex reveals enhanced control of immune RT surveillance."; RL Cell 174:300-311(2018). RN [21] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=29625897; DOI=10.1016/j.immuni.2018.03.016; RA Xia P., Wang S., Ye B., Du Y., Li C., Xiong Z., Qu Y., Fan Z.; RT "A circular RNA protects dormant hematopoietic stem cells from DNA sensor RT cGAS-mediated exhaustion."; RL Immunity 48:688-701(2018). RN [22] RP FUNCTION. RX PubMed=30356214; DOI=10.1038/s41586-018-0629-6; RA Liu H., Zhang H., Wu X., Ma D., Wu J., Wang L., Jiang Y., Fei Y., Zhu C., RA Tan R., Jungblut P., Pei G., Dorhoi A., Yan Q., Zhang F., Zheng R., Liu S., RA Liang H., Liu Z., Yang H., Chen J., Wang P., Tang T., Peng W., Hu Z., RA Xu Z., Huang X., Wang J., Li H., Zhou Y., Liu F., Yan D., Kaufmann S.H.E., RA Chen C., Mao Z., Ge B.; RT "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis."; RL Nature 563:131-136(2018). RN [23] RP UBIQUITINATION AT LYS-335, FUNCTION, SUBUNIT, ACTIVITY REGULATION, AND RP MUTAGENESIS OF LYS-278; LYS-335 AND LYS-350. RX PubMed=29426904; DOI=10.1038/s41467-018-02936-3; RA Seo G.J., Kim C., Shin W.J., Sklan E.H., Eoh H., Jung J.U.; RT "TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing."; RL Nat. Commun. 9:613-613(2018). RN [24] RP CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=29976794; DOI=10.1126/science.aat1022; RA Du M., Chen Z.J.; RT "DNA-induced liquid phase condensation of cGAS activates innate immune RT signaling."; RL Science 361:704-709(2018). RN [25] RP SUBCELLULAR LOCATION, AND LIPID-BINDING. RX PubMed=30827685; DOI=10.1016/j.cell.2019.01.049; RA Barnett K.C., Coronas-Serna J.M., Zhou W., Ernandes M.J., Cao A., RA Kranzusch P.J., Kagan J.C.; RT "Phosphoinositide interactions position cGAS at the plasma membrane to RT ensure efficient distinction between self- and viral DNA."; RL Cell 176:1432-1446(2019). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 211-GLU--ASP-213; RP ARG-222; LYS-240; ARG-241; 242-ILE--PRO-247; ARG-244; LYS-335; LYS-382; RP GLU-386 AND 395-LYS--LYS-399. RX PubMed=31808743; DOI=10.7554/elife.47491; RA Volkman H.E., Cambier S., Gray E.E., Stetson D.B.; RT "Tight nuclear tethering of cGAS is essential for preventing RT autoreactivity."; RL Elife 8:0-0(2019). RN [27] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=31544964; DOI=10.15252/embj.2019102718; RA Jiang H., Xue X., Panda S., Kawale A., Hooy R.M., Liang F., Sohn J., RA Sung P., Gekara N.O.; RT "Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates RT genome destabilization and cell death."; RL EMBO J. 38:e102718-e102718(2019). RN [28] RP PROTEOLYTIC CLEAVAGE. RX PubMed=30878284; DOI=10.1016/j.molcel.2019.02.013; RA Ning X., Wang Y., Jing M., Sha M., Lv M., Gao P., Zhang R., Huang X., RA Feng J.M., Jiang Z.; RT "Apoptotic caspases suppress type i interferon production via the cleavage RT of cGAS, MAVS, and IRF3."; RL Mol. Cell 74:19-31(2019). RN [29] RP PHOSPHORYLATION AT SER-291. RX PubMed=32351706; DOI=10.1038/s41421-020-0162-2; RA Zhong L., Hu M.M., Bian L.J., Liu Y., Chen Q., Shu H.B.; RT "Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis."; RL Cell Discov. 6:26-26(2020). RN [30] RP UBIQUITINATION AT LYS-271 AND LYS-464, DEUBIQUITINATION, AND MUTAGENESIS OF RP LYS-271 AND LYS-464. RX PubMed=32457395; DOI=10.1038/s41422-020-0341-6; RA Zhang Q., Tang Z., An R., Ye L., Zhong B.; RT "USP29 maintains the stability of cGAS and promotes cellular antiviral RT responses and autoimmunity."; RL Cell Res. 30:914-927(2020). RN [31] RP DEUBIQUITINATION. RX PubMed=31534008; DOI=10.4049/jimmunol.1900514; RA Guo Y., Jiang F., Kong L., Li B., Yang Y., Zhang L., Liu B., Zheng Y., RA Gao C.; RT "USP27X deubiquitinates and stabilizes the DNA sensor cGAS to regulate RT cytosolic DNA-mediated signaling."; RL J. Immunol. 203:2049-2054(2019). RN [32] RP ACTIVITY REGULATION. RX PubMed=32156810; DOI=10.1128/mbio.00136-20; RA Ma H., Qian W., Bambouskova M., Collins P.L., Porter S.I., Byrum A.K., RA Zhang R., Artyomov M., Oltz E.M., Mosammaparast N., Miner J.J., RA Diamond M.S.; RT "Barrier-to-autointegration factor 1 protects against a basal cGAS-STING RT response."; RL MBio 11:0-0(2020). RN [33] RP PHOSPHORYLATION AT SER-420, DEPHOSPHORYLATION, ACTIVITY REGULATION, AND RP MUTAGENESIS OF SER-420. RX PubMed=32474700; DOI=10.1007/s13238-020-00729-3; RA Li M., Shu H.B.; RT "Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity RT and innate antiviral response."; RL Protein Cell 11:584-599(2020). RN [34] RP FUNCTION. RX PubMed=33688080; DOI=10.1126/scisignal.aax7942; RA Apel F., Andreeva L., Knackstedt L.S., Streeck R., Frese C.K., Goosmann C., RA Hopfner K.P., Zychlinsky A.; RT "The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps."; RL Sci. Signal. 14:0-0(2021). RN [35] RP FUNCTION, METHYLATION AT LYS-491, INTERACTION WITH PARP1 AND SGF29, AND RP MUTAGENESIS OF TYR-201; 244-ARG--HIS-250; 275-LYS--LYS-278; RP 399-LYS--LYS-402; 491-LYS--ARG-497 AND LYS-491. RX PubMed=35210392; DOI=10.1038/s41413-022-00194-0; RA Xiao Y., Li J., Liao X., He Y., He T., Yang C., Jiang L., Jeon S.M., RA Lee J.H., Chen Y., Liu R., Chen Q.; RT "RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA RT repair."; RL Bone Res. 10:19-19(2022). RN [36] RP ADP-RIBOSYLATION AT GLU-176, AND MUTAGENESIS OF GLU-176. RX PubMed=35460603; DOI=10.1016/j.molcel.2022.03.034; RA Wang F., Zhao M., Chang B., Zhou Y., Wu X., Ma M., Liu S., Cao Y., RA Zheng M., Dang Y., Xu J., Chen L., Liu T., Tang F., Ren Y., Xu Z., Mao Z., RA Huang K., Luo M., Li J., Liu H., Ge B.; RT "Cytoplasmic PARP1 links the genome instability to the inhibition of RT antiviral immunity through PARylating cGAS."; RL Mol. Cell 0:0-0(2022). RN [37] RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 147-507 IN COMPLEXES WITH DNA; RP GMP; GTP; ATP; CYCLIC GMP-AMP; MAGNESIUM AND ZINC IONS, FUNCTION, COFACTOR, RP CATALYTIC ACTIVITY, AND DNA-BINDING. RX PubMed=23647843; DOI=10.1016/j.cell.2013.04.046; RA Gao P., Ascano M., Wu Y., Barchet W., Gaffney B.L., Zillinger T., RA Serganov A.A., Liu Y., Jones R.A., Hartmann G., Tuschl T., Patel D.J.; RT "Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by RT DNA-activated cyclic GMP-AMP synthase."; RL Cell 153:1094-1107(2013). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 142-507 IN COMPLEX WITH RP 2',3'-CGAMP AND ZINC, AND DOMAIN. RX PubMed=24332030; DOI=10.1016/j.immuni.2013.10.019; RA Li X., Shu C., Yi G., Chaton C.T., Shelton C.L., Diao J., Zuo X., Kao C.C., RA Herr A.B., Li P.; RT "Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced RT oligomerization."; RL Immunity 39:1019-1031(2013). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 147-507 IN COMPLEX WITH ZINC, AND RP SUBUNIT. RX PubMed=24462292; DOI=10.1016/j.celrep.2014.01.003; RA Zhang X., Wu J., Du F., Xu H., Sun L., Chen Z., Brautigam C.A., Zhang X., RA Chen Z.J.; RT "The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and RT undergoes switch-like conformational changes in the activation loop."; RL Cell Rep. 6:421-430(2014). RN [40] {ECO:0007744|PDB:5N6I} RP X-RAY CRYSTALLOGRAPHY (3.60 ANGSTROMS) OF 139-507 IN COMPLEX WITH ZINC AND RP DNA, FUNCTION, AND SUBUNIT. RX PubMed=28902841; DOI=10.1038/nature23890; RA Andreeva L., Hiller B., Kostrewa D., Lassig C., de Oliveira Mann C.C., RA Jan Drexler D., Maiser A., Gaidt M., Leonhardt H., Hornung V., RA Hopfner K.P.; RT "cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA RT ladders."; RL Nature 549:394-398(2017). RN [41] {ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE, ECO:0007744|PDB:5XZG} RP X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 147-507 IN COMPLEX WITH ZINC AND RP INHIBITOR RU.521, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=28963528; DOI=10.1038/s41467-017-00833-9; RA Vincent J., Adura C., Gao P., Luz A., Lama L., Asano Y., Okamoto R., RA Imaeda T., Aida J., Rothamel K., Gogakos T., Steinberg J., Reasoner S., RA Aso K., Tuschl T., Patel D.J., Glickman J.F., Ascano M.; RT "Small molecule inhibition of cGAS reduces interferon expression in primary RT macrophages from autoimmune mice."; RL Nat. Commun. 8:750-750(2017). RN [42] {ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM, ECO:0007744|PDB:7BUQ} RP X-RAY CRYSTALLOGRAPHY (2.13 ANGSTROMS) OF 61-507 IN COMPLEX WITH ZINC, RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=32814054; DOI=10.1016/j.celrep.2020.108053; RA Zhao Z., Ma Z., Wang B., Guan Y., Su X.D., Jiang Z.; RT "Mn2+ directly activates cGAS and structural analysis suggests Mn2+ Induces RT a noncanonical catalytic synthesis of 2'3'-cGAMP."; RL Cell Rep. 32:108053-108053(2020). RN [43] {ECO:0007744|PDB:6X59, ECO:0007744|PDB:6X5A, ECO:0007744|PDB:6XJD} RP STRUCTURE BY ELECTRON MICROSCOPY (2.98 ANGSTROMS) OF 142-507 IN COMPLEX RP WITH NUCLEOSOME CORE AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH RP NUCLEOSOMES, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND RP MUTAGENESIS OF ARG-222; LYS-238; LYS-240; ARG-241; ARG-244; LYS-315; RP LYS-323; LYS-335; ARG-341; ARG-342 AND LYS-382. RX PubMed=32911481; DOI=10.1038/s41586-020-2749-z; RA Zhao B., Xu P., Rowlett C.M., Jing T., Shinde O., Lei Y., West A.P., RA Liu W.R., Li P.; RT "The molecular basis of tight nuclear tethering and inactivation of cGAS."; RL Nature 587:673-677(2020). RN [44] {ECO:0007744|PDB:7A08} RP STRUCTURE BY ELECTRON MICROSCOPY (3.11 ANGSTROMS) OF 139-507 IN COMPLEX RP WITH NUCLEOSOME CORE AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH RP NUCLEOSOMES, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND RP MUTAGENESIS OF ARG-222; LYS-240; ARG-241; ARG-337; ARG-341 AND ARG-342. RX PubMed=32911480; DOI=10.1038/s41586-020-2748-0; RA Michalski S., de Oliveira Mann C.C., Stafford C.A., Witte G., Bartho J., RA Lammens K., Hornung V., Hopfner K.P.; RT "Structural basis for sequestration and autoinhibition of cGAS by RT chromatin."; RL Nature 587:678-682(2020). RN [45] {ECO:0007744|PDB:7JO9, ECO:0007744|PDB:7JOA} RP STRUCTURE BY ELECTRON MICROSCOPY (3.30 ANGSTROMS) OF 142-507 IN COMPLEX RP WITH NUCLEOSOME AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH NUCLEOSOMES, RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF RP ARG-222; LYS-240 AND ARG-241. RX PubMed=32913000; DOI=10.1126/science.abd0609; RA Boyer J.A., Spangler C.J., Strauss J.D., Cesmat A.P., Liu P., McGinty R.K., RA Zhang Q.; RT "Structural basis of nucleosome-dependent cGAS inhibition."; RL Science 370:450-454(2020). CC -!- FUNCTION: Nucleotidyltransferase that catalyzes the formation of cyclic CC GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate CC immunity (PubMed:23258413, PubMed:23647843, PubMed:23722158, CC PubMed:26829768, PubMed:28214358, PubMed:29625897, PubMed:29426904, CC PubMed:32814054). Catalysis involves both the formation of a 2',5' CC phosphodiester linkage at the GpA step and the formation of a 3',5' CC phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] CC (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, CC PubMed:28214358). Acts as a key DNA sensor: directly binds double- CC stranded DNA (dsDNA), inducing the formation of liquid-like droplets in CC which CGAS is activated, leading to synthesis of 2',3'-cGAMP, a second CC messenger that binds to and activates STING1, thereby triggering type-I CC interferon production (PubMed:23722158, PubMed:28314590, CC PubMed:28363908, PubMed:28095500). Preferentially binds long dsDNA CC (around 45 bp) and forms ladder-like networks that function CC cooperatively to stabilize individual cGAS-dsDNA complexes CC (PubMed:28902841). Acts as a key foreign DNA sensor, the presence of CC double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that CC triggers the immune responses (PubMed:23722158, PubMed:28314590, CC PubMed:28363908). Has antiviral activity by sensing the presence of CC dsDNA from DNA viruses in the cytoplasm (PubMed:23258413, CC PubMed:23722158, PubMed:23647843). Also acts as an innate immune sensor CC of infection by retroviruses by detecting the presence of reverse- CC transcribed DNA in the cytosol (PubMed:23929945). Detection of CC retroviral reverse-transcribed DNA in the cytosol may be indirect and CC be mediated via interaction with PQBP1, which directly binds reverse- CC transcribed retroviral DNA (By similarity). Also detects the presence CC of DNA from bacteria (By similarity). 2',3'-cGAMP can be transferred CC from producing cells to neighboring cells through gap junctions, CC leading to promote STING1 activation and convey immune response to CC connecting cells (PubMed:24077100). 2',3'-cGAMP can also be transferred CC between cells by virtue of packaging within viral particles CC contributing to IFN-induction in newly infected cells in a cGAS- CC independent but STING1-dependent manner (PubMed:26229117). Also senses CC the presence of neutrophil extracellular traps (NETs) that are CC translocated to the cytosol following phagocytosis, leading to CC synthesis of 2',3'-cGAMP (PubMed:33688080). In addition to foreign DNA, CC can also be activated by endogenous nuclear or mitochondrial DNA (By CC similarity). When self-DNA leaks into the cytosol during cellular CC stress (such as mitochondrial stress, DNA damage, mitotic arrest or CC senescence), or is present in form of cytosolic micronuclei, CGAS is CC activated leading to a state of sterile inflammation (PubMed:28738408, CC PubMed:28759028). Acts as a regulator of cellular senescence by binding CC to cytosolic chromatin fragments that are present in senescent cells, CC leading to trigger type-I interferon production via STING1 and promote CC cellular senescence (PubMed:28759028). Also involved in the CC inflammatory response to genome instability and double-stranded DNA CC breaks: acts by localizing to micronuclei arising from genome CC instability (PubMed:28738408). Micronuclei, which as frequently found CC in cancer cells, consist of chromatin surrounded by its own nuclear CC membrane: following breakdown of the micronuclear envelope, a process CC associated with chromothripsis, CGAS binds self-DNA exposed to the CC cytosol, leading to 2',3'-cGAMP synthesis and subsequent activation of CC STING1 and type-I interferon production (PubMed:28738408). In a healthy CC cell, CGAS is however kept inactive even in cellular events that CC directly expose it to self-DNA, such as mitosis, when cGAS associates CC with chromatin directly after nuclear envelope breakdown or remains in CC the form of postmitotic persistent nuclear cGAS pools bound to CC chromatin (By similarity). Nuclear CGAS is inactivated by chromatin via CC direct interaction with nucleosomes, which block CGAS from DNA binding CC and thus prevent CGAS-induced autoimmunity (PubMed:31808743, CC PubMed:32911481, PubMed:32911480, PubMed:32913000). Also acts as a CC suppressor of DNA repair in response to DNA damage: inhibits homologous CC recombination repair by interacting with PARP1, the CGAS-PARP1 CC interaction leading to impede the formation of the PARP1-TIMELESS CC complex (PubMed:30356214, PubMed:31544964, PubMed:35210392). In CC addition to DNA, also sense translation stress: in response to CC translation stress, translocates to the cytosol and associates with CC collided ribosomes, promoting its activation and triggering type-I CC interferon production (By similarity). {ECO:0000250|UniProtKB:Q8N884, CC ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23647843, CC ECO:0000269|PubMed:23722158, ECO:0000269|PubMed:23929945, CC ECO:0000269|PubMed:24077100, ECO:0000269|PubMed:26229117, CC ECO:0000269|PubMed:26829768, ECO:0000269|PubMed:28095500, CC ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590, CC ECO:0000269|PubMed:28363908, ECO:0000269|PubMed:28738408, CC ECO:0000269|PubMed:28759028, ECO:0000269|PubMed:28902841, CC ECO:0000269|PubMed:29426904, ECO:0000269|PubMed:29625897, CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:31544964, CC ECO:0000269|PubMed:31808743, ECO:0000269|PubMed:32814054, CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, CC ECO:0000269|PubMed:32913000, ECO:0000269|PubMed:33688080, CC ECO:0000269|PubMed:35210392}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + GTP = 2',3'-cGAMP + 2 diphosphate; Xref=Rhea:RHEA:42064, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:143093; EC=2.7.7.86; CC Evidence={ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:28963528, CC ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416, CC ECO:0000269|PubMed:32814054}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42065; CC Evidence={ECO:0000269|PubMed:23258413}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:23647843}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:32814054}; CC Note=Binds 1 Mg(2+) per subunit (PubMed:23647843). Is also active with CC Mn(2+) (PubMed:23647843, PubMed:32814054). Mn(2+)-activated enzyme CC forms an inverted pppGp(2'-5')A intermediate, suggesting a non- CC canonical but accelerated 2',3'-cGAMP cyclization without substrate CC flip-over (PubMed:32814054). Mn(2+) ions are coordinated by CC triphosphate moiety of the inverted substrate, independent of the CC catalytic triad residues (PubMed:32814054). CC {ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:32814054}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:32814054, CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, CC ECO:0000269|PubMed:32913000}; CC Note=Undergoes a liquid-like phase transition after binding to DNA, CC which is dependent on zinc. {ECO:0000250|UniProtKB:Q8N884}; CC -!- ACTIVITY REGULATION: The enzyme activity is strongly increased by CC double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA (By CC similarity). DNA-binding induces the formation of liquid-like droplets CC in which CGAS is activated (By similarity). Liquid-like droplets also CC create a selective environment that restricts entry of negative CC regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA (By CC similarity). A number of mechanisms exist to restrict its activity CC toward self-DNA (PubMed:32911481, PubMed:32911480, PubMed:32913000). CC The nucleotidyltransferase activity is inhibited in the nucleus via its CC association with nucleosomes: interacts with the acidic patch of CC histones H2A and H2B, thereby blocking DNA-binding and subsequent CC activation (PubMed:32156810, PubMed:32911481, PubMed:32911480, CC PubMed:32913000). CGAS is also inactive when associated with mitotic CC chromatin (By similarity). Chromatin-bound CGAS cannot be activated by CC exogenous DNA in mitotic cells: phosphorylation of the N-terminal CC disordered part by AURKB during the G2-M transition blocks CGAS liquid CC phase separation and activation (By similarity). Activity toward self- CC DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane CC integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby CC preventing CGAS activation (PubMed:32156810). DNA-induced activation at CC micronuclei is also limited by TREX1, which degrades micronuclear DNA CC upon nuclear envelope rupture, thereby preventing CGAS activation (By CC similarity). Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the CC cyclic GMP-AMP synthase activity (By similarity). Acetylation by KAT5 CC increases the cyclic GMP-AMP synthase activity by promoting DNA-binding CC and subsequent activation (By similarity). Phosphorylation at Ser-291 CC suppresses the nucleotidyltransferase activity (PubMed:26440888). CC Phosphorylation at Ser-420 promotes the cyclic GMP-AMP synthase CC activity (PubMed:32474700). Phosphorylation at Thr-52 and Ser-199 CC inhibits its cyclic GMP-AMP synthase activity (By similarity). CC Ubiquitination at Lys-372 via 'Lys-27'-linked polyubiquitination CC enhances the cyclic GMP-AMP synthase activity (By similarity). CC Monoubiquitination at Lys-335 promotes oligomerization and subsequent CC activation (PubMed:29426904). Sumoylation at Lys-335, Lys-372 and Lys- CC 382 prevents DNA-binding, oligomerization and nucleotidyltransferase CC activity (PubMed:28095500). The enzyme activity is impaired by the CC cleavage by CASP1 (PubMed:28314590). In addition to DNA, also activated CC by collided ribosomes upon translation stress: specifically binds CC collided ribosomes, promoting its activation and triggering type-I CC interferon production (By similarity). In hematopoietic stem cells, CC binding to circular RNA cia-cGAS inhibits the cyclic GMP-AMP synthase CC activity (PubMed:29625897). Strongly inhibited by compound RU.521, CC which is specific for mouse protein (PubMed:28963528, PubMed:30007416). CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:26440888, CC ECO:0000269|PubMed:28095500, ECO:0000269|PubMed:28314590, CC ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:29426904, CC ECO:0000269|PubMed:29625897, ECO:0000269|PubMed:30007416, CC ECO:0000269|PubMed:32156810, ECO:0000269|PubMed:32474700, CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, CC ECO:0000269|PubMed:32913000}. CC -!- SUBUNIT: Monomer in the absence of DNA (PubMed:28214358). Homodimer in CC presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two CC DNA molecules (PubMed:29426904, PubMed:28902841). Interacts with CC nucleosomes; interaction is mainly mediated via histones H2A and H2B CC and inactivates the nucleotidyltransferase activity by blocking DNA- CC binding and subsequent activation (PubMed:32911481, PubMed:32911480, CC PubMed:32913000). Interacts with PQBP1 (via WW domain) (By similarity). CC Interacts with TRIM14; this interaction recruits USP14, leading to CC deubiquitinate and stabilize CGAS and promote type I interferon CC production (By similarity). Interacts with ZCCHC3; promoting sensing of CC dsDNA by CGAS (By similarity). Interacts (when not monomethylated) with CC (poly-ADP-ribosylated) PARP1; interaction takes place in the nucleus CC and prevents the formation of the PARP1-TIMELESS complex CC (PubMed:35210392). Interacts (when monomethylated) with SGF29; CC interaction with SGF29 prevents interaction with PARP1 CC (PubMed:35210392). Interacts with PCBP2; preventing the formation of CC liquid-like droplets in which CGAS is activated (By similarity). CC Interacts with Irgm1; promoting CGAS degradation (By similarity). CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:28214358, CC ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:29426904, CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, CC ECO:0000269|PubMed:32913000, ECO:0000269|PubMed:35210392}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:31544964, CC ECO:0000269|PubMed:31808743}. Chromosome {ECO:0000269|PubMed:31544964, CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, CC ECO:0000269|PubMed:32913000}. Cell membrane CC {ECO:0000269|PubMed:30827685}; Peripheral membrane protein CC {ECO:0000269|PubMed:30827685}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:31544964, CC ECO:0000269|PubMed:31808743}. Note=Mainly localizes in the nucleus, and CC at low level in the cytosol (PubMed:31808743, PubMed:31544964). On CC chromosomes, enriched on centromeric satellite and LINE DNA repeat CC elements (By similarity). Exported from the nucleus to the cytosol in a CC XPO1/CRM1 via the nuclear export signal in response to DNA stimulation CC (By similarity). Outside the nucleus, localizes at the cell membrane as CC a peripheral membrane protein in resting conditions: association to the CC cell membrane is mediated via binding to phosphatidylinositol 4,5- CC bisphosphate (PtdIns(4,5)P2) (PubMed:30827685). Localization at the CC cell membrane is required to limit the recognition of self-DNA (By CC similarity). Following detection of double-stranded DNA (dsDNA), CC released from the cell membrane into the cytosol in order to signal (By CC similarity). Upon transfection with dsDNA forms punctate structures CC that co-localize with DNA and Beclin-1 (BECN1) (By similarity). CC Phosphorylation at Tyr-201 promotes cytosolic retention (By CC similarity). In response to translation stress, translocates to the CC cytosol and associates with collided ribosomes (By similarity). CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:30827685, CC ECO:0000269|PubMed:31544964, ECO:0000269|PubMed:31808743}. CC -!- DOMAIN: The N-terminal disordered part (1-146) binds unspecifically CC dsDNA and expand the binding and moving range of CGAS on dsDNA CC (PubMed:28214358, PubMed:28314590, PubMed:28363908). The disordered and CC positively charged residues enhance CGAS-DNA phase separation by CC increasing the valencies of DNA-binding (By similarity). The N-terminus CC is required to sense chromatin and its phosphorylation blocks its CC activation by chromatin DNA (By similarity). When the N-terminal part CC (1-146) is missing the protein bound to dsDNA homodimerizes CC (PubMed:28214358). {ECO:0000250|UniProtKB:Q8N884, CC ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590, CC ECO:0000269|PubMed:28363908}. CC -!- DOMAIN: The arginine-anchor tightly binds to the canonical H2A acidic- CC patch residues. {ECO:0000269|PubMed:32911480, CC ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32913000}. CC -!- PTM: The N-terminal disordered part (1-146) is phosphorylated by AURKB CC during the G2-M transition, blocking CGAS liquid phase separation and CC preventing activation (By similarity). Phosphorylation at Tyr-201 by CC BLK promotes cytosolic retention (By similarity). Localizes into the CC nucleus following dephosphorylation at Tyr-201 (By similarity). CC Phosphorylation at Ser-420 activates the nucleotidyltransferase CC activity (PubMed:32474700). Dephosphorylation at Ser-420 by PPP6C CC impairs its ability to bind GTP, thereby inactivating it CC (PubMed:32474700). Phosphorylation at Thr-52 and Ser-199 by PRKDC CC inhibits its cyclic GMP-AMP synthase activity by impairing CC homodimerization and activation (By similarity). Phosphorylation at CC Ser-291 by AKT (AKT1, AKT2 or AKT3) suppresses the CC nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at CC Ser-291 by CDK1 during mitosis leads to its inhibition, thereby CC preventing CGAS activation by self-DNA during mitosis CC (PubMed:32351706). Dephosphorylated at Ser-291 by protein phosphatase CC PP1 upon mitotic exit (PubMed:32351706). {ECO:0000250|UniProtKB:Q8N884, CC ECO:0000269|PubMed:26440888, ECO:0000269|PubMed:32351706, CC ECO:0000269|PubMed:32474700}. CC -!- PTM: Ubiquitinated at Lys-402 via 'Lys-48'-linked polyubiquitin chains, CC leading to its SQSTM1-mediated autophagic degradation (By similarity). CC Interaction with TRIM14 promotes recruitment of USP14, leading to CC deubiquitinate Lys-402 and stabilize CGAS (By similarity). CC Ubiquitinated at Lys-372 by RNF185 via 'Lys-27'-linked CC polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity (By CC similarity). Monoubiquitination at Lys-335 by TRIM56 promotes CC oligomerization and subsequent activation (PubMed:29426904). CC Monoubiquitination by TRIM41 promotes CGAS activation (By similarity). CC Ubiquitination at Lys-271 and Lys-464 via 'Lys-48'-linked CC polyubiquitination promotes its degradation (PubMed:32457395, CC PubMed:27637147). Deubiquitination at Lys-271 by USP29 promotes its CC stabilization (PubMed:32457395). Deubiquitinated by USP27X, promoting CC its stabilization (PubMed:31534008). Ubiquitinated at Lys-399 via 'Lys- CC 63'-linked polyubiquitin chains by MARCHF8, leading to the inhibition CC of its DNA binding ability (By similarity). CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:27637147, CC ECO:0000269|PubMed:29426904, ECO:0000269|PubMed:31534008, CC ECO:0000269|PubMed:32457395}. CC -!- PTM: Sumoylated at Lys-217 and Lys-464 by TRIM38 in uninfected cells CC and during the early phase of viral infection, promoting its stability CC by preventing ubiquitination at Lys-271 and Lys-464, and subsequent CC degradation (PubMed:27637147). Desumoylated by SENP2 during the late CC phase of viral infection (PubMed:27637147). Sumoylation at Lys-335, CC Lys-372 and Lys-382 prevents DNA-binding, oligomerization and CC nucleotidyltransferase activity (PubMed:28095500). Desumoylation at CC Lys-335, Lys-372 and Lys-382 by SENP7 relieves inhibition and activates CC CGAS (PubMed:28095500). {ECO:0000269|PubMed:27637147, CC ECO:0000269|PubMed:28095500}. CC -!- PTM: Polyglutamylated by TTLL6 at Glu-272, leading to impair DNA- CC binding activity. Monoglutamylated at Glu-302 by TTLL4, leading to CC impair the nucleotidyltransferase activity. Deglutamylated by CC AGBL5/CCP5 and AGBL6/CCP6. {ECO:0000269|PubMed:26829768}. CC -!- PTM: Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the cyclic CC GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge CC such as viral infections. Acetylation by KAT5 increases the cyclic GMP- CC AMP synthase activity by promoting DNA-binding and subsequent CC activation. {ECO:0000250|UniProtKB:Q8N884}. CC -!- PTM: Proteolytically cleaved by apoptotic caspases during apoptosis, CC leading to its inactivation (PubMed:25525874, PubMed:30878284). The CC damage of the nucleus and the mitochondria during apoptosis leads to CC leakage of nuclear and mitochondrial DNA, which activate CGAS: cleavage CC and inactivation during apoptosis in required to prevent cytokine CC overproduction (PubMed:25525874). Cleaved by CASP7 and CASP3 during CC virus-induced apoptosis, thereby inactivating it and preventing CC cytokine overproduction (PubMed:30878284). Cleaved by CASP1 upon DNA CC virus infection; the cleavage impairs cGAMP production CC (PubMed:28314590). Also cleaved by the pyroptotic CASP4 during non- CC canonical inflammasome activation; does not cut at the same sites than CC CASP1 (PubMed:28314590). {ECO:0000269|PubMed:25525874, CC ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:30878284}. CC -!- PTM: Degraded via selective autophagy following interaction with Irgm1. CC Irgm1 promotes CGAS recruitment to autophagosome membranes, promoting CC its SQSTM1/p62-dependent autophagic degradation. CC {ECO:0000250|UniProtKB:Q8N884}. CC -!- PTM: Poly-ADP-ribosylation at Glu-176 by PARP1 impairs DNA-binding, CC thereby preventing the cyclic GMP-AMP synthase activity. CC {ECO:0000269|PubMed:35460603}. CC -!- PTM: Palmitoylation at Cys-459 by ZDHHC18 impairs DNA-binding, thereby CC preventing the cyclic GMP-AMP synthase activity (By similarity). CC Palmitoylation at Cys-392 and Cys-393 by ZDHHC9 promotes CC homodimerization and cyclic GMP-AMP synthase activity (By similarity). CC Depalmitoylation at Cys-392 and Cys-393 by LYPLAL1 impairs CC homodimerization and cyclic GMP-AMP synthase activity (By similarity). CC {ECO:0000250|UniProtKB:Q8N884}. CC -!- PTM: Monomethylated at Lys-491 by SETD7 (PubMed:35210392). CC Monomethylation promotes interaction with SGF29, preventing interaction CC between PARP1 nad SGF29 (PubMed:35210392). Demethylation by RIOX1 CC promotes interaction with PARP1, followed by PARP1 inactivation CC (PubMed:35210392). {ECO:0000269|PubMed:35210392}. CC -!- SIMILARITY: Belongs to the mab-21 family. {ECO:0000305}. CC -!- CAUTION: Was reported to homodimerize in presence of double-stranded CC DNA (dsDNA) (PubMed:24332030). However, this result was based on a CC structure lacking the N-terminal part (1-146), which caused CC homodimerization in presence of dsDNA (PubMed:28214358). CC {ECO:0000269|PubMed:24332030}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; KC294567; AGB51854.1; -; mRNA. DR EMBL; AK054330; BAC35733.1; -; mRNA. DR EMBL; AK145268; BAE26335.1; -; mRNA. DR EMBL; AC158987; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH466522; EDL26396.1; -; Genomic_DNA. DR EMBL; BC052196; AAH52196.1; -; mRNA. DR EMBL; BC145651; AAI45652.1; -; mRNA. DR EMBL; BC145653; AAI45654.1; -; mRNA. DR CCDS; CCDS40702.1; -. DR RefSeq; NP_775562.2; NM_173386.5. DR PDB; 4K8V; X-ray; 2.00 A; A/B/C/D=147-507. DR PDB; 4K96; X-ray; 2.08 A; A/B=147-507. DR PDB; 4K97; X-ray; 2.41 A; A=147-507. DR PDB; 4K98; X-ray; 1.94 A; A=147-507. DR PDB; 4K99; X-ray; 1.95 A; A=147-507. DR PDB; 4K9A; X-ray; 2.26 A; A=147-507. DR PDB; 4K9B; X-ray; 2.26 A; A=147-507. DR PDB; 4LEY; X-ray; 2.50 A; A/B/C/D=142-507. DR PDB; 4LEZ; X-ray; 2.36 A; A/C=142-507. DR PDB; 4O6A; X-ray; 1.86 A; A/B=147-507. DR PDB; 5N6I; X-ray; 3.60 A; A/B/C/D/E/F=139-507. DR PDB; 5XZB; X-ray; 2.13 A; A=149-505. DR PDB; 5XZE; X-ray; 2.18 A; A=147-507. DR PDB; 5XZG; X-ray; 1.83 A; A=147-507. DR PDB; 6X59; EM; 2.98 A; K=142-507. DR PDB; 6X5A; EM; 4.36 A; K=142-507. DR PDB; 6XJD; EM; 6.80 A; K/L=142-507. DR PDB; 7A08; EM; 3.11 A; a=139-507. DR PDB; 7BUJ; X-ray; 2.13 A; A/B=61-507. DR PDB; 7BUM; X-ray; 3.05 A; A/B=1-507. DR PDB; 7BUQ; X-ray; 3.09 A; A/B=1-507. DR PDB; 7JO9; EM; 3.30 A; K=142-507. DR PDB; 7JOA; EM; 3.30 A; K=142-507. DR PDB; 7KXS; X-ray; 2.60 A; A/B=147-507. DR PDB; 7UTT; X-ray; 2.04 A; A/C=147-507. DR PDB; 7UUX; X-ray; 2.26 A; A/C=147-507. DR PDB; 7UXW; X-ray; 2.57 A; A/C=147-507. DR PDB; 7UYQ; X-ray; 2.57 A; A/C=147-507. DR PDB; 7UYZ; X-ray; 2.49 A; A/C=147-507. DR PDB; 7UZR; X-ray; 2.70 A; A/C=147-507. DR PDB; 7V0C; X-ray; 2.57 A; A/C=147-507. DR PDB; 7V0R; X-ray; 2.51 A; A/C=147-507. DR PDB; 7V0W; X-ray; 2.66 A; A/C=147-507. DR PDB; 8EAE; X-ray; 2.56 A; A/C=147-507. DR PDBsum; 4K8V; -. DR PDBsum; 4K96; -. DR PDBsum; 4K97; -. DR PDBsum; 4K98; -. DR PDBsum; 4K99; -. DR PDBsum; 4K9A; -. DR PDBsum; 4K9B; -. DR PDBsum; 4LEY; -. DR PDBsum; 4LEZ; -. DR PDBsum; 4O6A; -. DR PDBsum; 5N6I; -. DR PDBsum; 5XZB; -. DR PDBsum; 5XZE; -. DR PDBsum; 5XZG; -. DR PDBsum; 6X59; -. DR PDBsum; 6X5A; -. DR PDBsum; 6XJD; -. DR PDBsum; 7A08; -. DR PDBsum; 7BUJ; -. DR PDBsum; 7BUM; -. DR PDBsum; 7BUQ; -. DR PDBsum; 7JO9; -. DR PDBsum; 7JOA; -. DR PDBsum; 7KXS; -. DR PDBsum; 7UTT; -. DR PDBsum; 7UUX; -. DR PDBsum; 7UXW; -. DR PDBsum; 7UYQ; -. DR PDBsum; 7UYZ; -. DR PDBsum; 7UZR; -. DR PDBsum; 7V0C; -. DR PDBsum; 7V0R; -. DR PDBsum; 7V0W; -. DR PDBsum; 8EAE; -. DR AlphaFoldDB; Q8C6L5; -. DR EMDB; EMD-11601; -. DR EMDB; EMD-22046; -. DR EMDB; EMD-22047; -. DR EMDB; EMD-22206; -. DR EMDB; EMD-22408; -. DR EMDB; EMD-22409; -. DR SMR; Q8C6L5; -. DR BioGRID; 229561; 1. DR STRING; 10090.ENSMUSP00000063331; -. DR BindingDB; Q8C6L5; -. DR ChEMBL; CHEMBL4523383; -. DR iPTMnet; Q8C6L5; -. DR PhosphoSitePlus; Q8C6L5; -. DR EPD; Q8C6L5; -. DR MaxQB; Q8C6L5; -. DR PaxDb; 10090-ENSMUSP00000063331; -. DR ProteomicsDB; 281655; -. DR Pumba; Q8C6L5; -. DR Antibodypedia; 31341; 297 antibodies from 32 providers. DR DNASU; 214763; -. DR Ensembl; ENSMUST00000070742.14; ENSMUSP00000063331.8; ENSMUSG00000032344.18. DR GeneID; 214763; -. DR KEGG; mmu:214763; -. DR UCSC; uc009quj.2; mouse. DR AGR; MGI:2442261; -. DR CTD; 115004; -. DR MGI; MGI:2442261; Cgas. DR VEuPathDB; HostDB:ENSMUSG00000032344; -. DR eggNOG; KOG3963; Eukaryota. DR GeneTree; ENSGT01050000244827; -. DR HOGENOM; CLU_040428_2_0_1; -. DR InParanoid; Q8C6L5; -. DR OMA; EHYFIPG; -. DR OrthoDB; 2967429at2759; -. DR PhylomeDB; Q8C6L5; -. DR TreeFam; TF331255; -. DR BRENDA; 2.7.7.86; 3474. DR BioGRID-ORCS; 214763; 2 hits in 75 CRISPR screens. DR ChiTaRS; Cgas; mouse. DR PRO; PR:Q8C6L5; -. DR Proteomes; UP000000589; Chromosome 9. DR RNAct; Q8C6L5; Protein. DR Bgee; ENSMUSG00000032344; Expressed in secondary oocyte and 118 other cell types or tissues. DR ExpressionAtlas; Q8C6L5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0016604; C:nuclear body; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB. DR GO; GO:0061501; F:2',3'-cyclic GMP-AMP synthase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0140693; F:molecular condensate scaffold activity; ISS:UniProtKB. DR GO; GO:0031491; F:nucleosome binding; IDA:UniProtKB. DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:UniProtKB. DR GO; GO:0160004; F:poly-ADP-D-ribose modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB. DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:UniProtKB. DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IDA:UniProtKB. DR GO; GO:0140896; P:cGAS/STING signaling pathway; ISO:MGI. DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:UniProtKB. DR GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; ISO:MGI. DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB. DR GO; GO:0008340; P:determination of adult lifespan; IGI:MGI. DR GO; GO:0006974; P:DNA damage response; ISS:UniProtKB. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; ISO:MGI. DR GO; GO:0160049; P:negative regulation of cGAS/STING signaling pathway; ISO:MGI. DR GO; GO:0045738; P:negative regulation of DNA repair; IDA:UniProt. DR GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB. DR GO; GO:0038001; P:paracrine signaling; IDA:UniProtKB. DR GO; GO:0002221; P:pattern recognition receptor signaling pathway; ISO:MGI. DR GO; GO:2000774; P:positive regulation of cellular senescence; IDA:UniProtKB. DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IDA:UniProtKB. DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB. DR GO; GO:0050776; P:regulation of immune response; IGI:MGI. DR GO; GO:0002637; P:regulation of immunoglobulin production; IGI:MGI. DR GO; GO:0050863; P:regulation of T cell activation; IGI:MGI. DR GO; GO:0032479; P:regulation of type I interferon production; IGI:MGI. DR Gene3D; 1.10.1410.40; -; 1. DR Gene3D; 3.30.460.90; -; 1. DR InterPro; IPR024810; Mab-21-like. DR InterPro; IPR046903; Mab-21-like_nuc_Trfase. DR InterPro; IPR046906; Mab-21_HhH/H2TH-like. DR PANTHER; PTHR10656; CELL FATE DETERMINING PROTEIN MAB21-RELATED; 1. DR PANTHER; PTHR10656:SF35; CYCLIC GMP-AMP SYNTHASE; 1. DR Pfam; PF03281; Mab-21; 1. DR Pfam; PF20266; Mab-21_C; 1. DR SMART; SM01265; Mab-21; 1. DR Genevisible; Q8C6L5; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; ADP-ribosylation; Antiviral defense; KW ATP-binding; Cell membrane; Chromosome; Cytoplasm; DNA damage; DNA repair; KW DNA-binding; GTP-binding; Immunity; Innate immunity; Isopeptide bond; KW Lipid-binding; Lipoprotein; Magnesium; Membrane; Metal-binding; KW Methylation; Nucleotide-binding; Nucleotidyltransferase; Nucleus; KW Palmitate; Phosphoprotein; Reference proteome; Transferase; KW Ubl conjugation; Zinc. FT CHAIN 1..507 FT /note="Cyclic GMP-AMP synthase" FT /id="PRO_0000421764" FT REGION 1..151 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1..146 FT /note="DNA-binding" FT /evidence="ECO:0000269|PubMed:28363908" FT REGION 48..59 FT /note="Required for association with the cell membrane" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT REGION 119..132 FT /note="Required for activation upon DNA viral infection" FT /evidence="ECO:0000269|PubMed:28314590" FT REGION 158..201 FT /note="DNA-binding" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0007744|PDB:5N6I" FT REGION 329..370 FT /note="Interaction with collided ribosomes" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT REGION 372..395 FT /note="DNA-binding" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0007744|PDB:5N6I" FT MOTIF 154..159 FT /note="Nuclear export signal" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOTIF 281..291 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT COMPBIAS 38..61 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 197 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 199 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 211 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 213 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /evidence="ECO:0000269|PubMed:24332030, FT ECO:0007744|PDB:4LEZ" FT BINDING 213 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 290 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /evidence="ECO:0000269|PubMed:24332030, FT ECO:0007744|PDB:4LEZ" FT BINDING 307 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /evidence="ECO:0000269|PubMed:24332030, FT ECO:0007744|PDB:4LEZ" FT BINDING 307 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 307 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 350 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /evidence="ECO:0000269|PubMed:24332030, FT ECO:0007744|PDB:4LEZ" FT BINDING 364..371 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 364..366 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /evidence="ECO:0000269|PubMed:24332030, FT ECO:0007744|PDB:4LEZ" FT BINDING 371 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 378 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I, FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE, FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6X59, FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM, FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9, FT ECO:0007744|PDB:7JOA" FT BINDING 384 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I, FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE, FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6X59, FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM, FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9, FT ECO:0007744|PDB:7JOA" FT BINDING 385 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I, FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE, FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6XJD, FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM, FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9, FT ECO:0007744|PDB:7JOA" FT BINDING 392 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:23647843, FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292, FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528, FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911480, FT ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32913000, FT ECO:0007744|PDB:5N6I, ECO:0007744|PDB:5XZB, FT ECO:0007744|PDB:5XZE, ECO:0007744|PDB:5XZG, FT ECO:0007744|PDB:6X5A, ECO:0007744|PDB:7BUJ, FT ECO:0007744|PDB:7BUM, ECO:0007744|PDB:7BUQ, FT ECO:0007744|PDB:7JO9, ECO:0007744|PDB:7JOA" FT BINDING 402 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23647843" FT BINDING 420..424 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23647843" FT SITE 241 FT /note="Arginine-anchor" FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000" FT SITE 307..308 FT /note="Cleavage; by CASP3" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 52 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 176 FT /note="PolyADP-ribosyl glutamic acid" FT /evidence="ECO:0000269|PubMed:35460603" FT MOD_RES 199 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 201 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 272 FT /note="5-glutamyl polyglutamate" FT /evidence="ECO:0000269|PubMed:26829768" FT MOD_RES 291 FT /note="Phosphoserine; by CDK1 and PKB" FT /evidence="ECO:0000269|PubMed:26440888, FT ECO:0000269|PubMed:32351706" FT MOD_RES 302 FT /note="5-glutamyl glutamate" FT /evidence="ECO:0000269|PubMed:26829768" FT MOD_RES 372 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 382 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 402 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT MOD_RES 420 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:32474700" FT MOD_RES 491 FT /note="N6-methyllysine" FT /evidence="ECO:0000269|PubMed:35210392" FT LIPID 392 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT LIPID 393 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT LIPID 459 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT CROSSLNK 217 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:27637147" FT CROSSLNK 271 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27637147, FT ECO:0000269|PubMed:32457395" FT CROSSLNK 335 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000269|PubMed:28095500" FT CROSSLNK 335 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:29426904" FT CROSSLNK 372 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000269|PubMed:28095500" FT CROSSLNK 372 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT CROSSLNK 382 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:28095500" FT CROSSLNK 399 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT CROSSLNK 402 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q8N884" FT CROSSLNK 464 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000269|PubMed:27637147" FT CROSSLNK 464 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:27637147, FT ECO:0000269|PubMed:32457395" FT MUTAGEN 172 FT /note="N->K: Induces alteration of the DNA-binding surface FT and leads to decreased synthesis of cyclic GMP-AMP (cGAMP); FT when associated with L-180." FT /evidence="ECO:0000269|PubMed:30007416" FT MUTAGEN 176 FT /note="E->A: Abolished poly-ADP-ribosylation by PARP1, FT stimulating interferon production in knockin mice." FT /evidence="ECO:0000269|PubMed:35460603" FT MUTAGEN 180 FT /note="R->L: Induces alteration of the DNA-binding surface FT and leads to decreased synthesis of cyclic GMP-AMP (cGAMP); FT when associated with K-182." FT /evidence="ECO:0000269|PubMed:30007416" FT MUTAGEN 198 FT /note="G->A: Abolishes stimulation of interferon FT production; when associated with A-199." FT /evidence="ECO:0000269|PubMed:26229117" FT MUTAGEN 199 FT /note="S->A: Abolishes stimulation of interferon FT production; when associated with A-199." FT /evidence="ECO:0000269|PubMed:26229117" FT MUTAGEN 201 FT /note="Y->E: Phosphomimetic mutant; reduced translocation FT to the nucleus following treatment with etoposide." FT /evidence="ECO:0000269|PubMed:35210392" FT MUTAGEN 211..213 FT /note="EFD->AFA: Abolished nucleotidyltransferase activity. FT Does not affect nuclear localization and tethering to FT chromatin." FT /evidence="ECO:0000269|PubMed:31808743" FT MUTAGEN 211 FT /note="E->A: Abolishes ability to promote type-I interferon FT production." FT /evidence="ECO:0000269|PubMed:23258413" FT MUTAGEN 213 FT /note="D->A: Abolishes ability to promote type-I interferon FT production." FT /evidence="ECO:0000269|PubMed:23258413" FT MUTAGEN 217 FT /note="K->R: Reduced sumoylation." FT /evidence="ECO:0000269|PubMed:27637147" FT MUTAGEN 222 FT /note="R->E: Impaired tethering to chromatin, leading to FT constitutive activation in the absence of DNA." FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000" FT MUTAGEN 238 FT /note="K->E: Does not affect interaction with nucleosomes." FT /evidence="ECO:0000269|PubMed:32911481" FT MUTAGEN 240 FT /note="K->E: Impaired tethering to chromatin, leading to FT constitutive activation in the absence of DNA." FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000" FT MUTAGEN 241 FT /note="R->E: Abolished tethering to chromatin, leading to FT strong constitutive activation in the absence of DNA." FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481, FT ECO:0000269|PubMed:32913000" FT MUTAGEN 242..247 FT /note="IPRGNP->SGSGSG: Slightly decreased tethering to FT chromatin, leading to mild constitutive activation in the FT absence of DNA." FT /evidence="ECO:0000269|PubMed:31808743" FT MUTAGEN 244..250 FT /note="RGNPLSH->AGNPLSA: Does not affect ability to bind FT poly-ADP-ribosylated PARP1." FT /evidence="ECO:0000269|PubMed:35210392" FT MUTAGEN 244 FT /note="R->E: Slightly decreased tethering to chromatin. FT Does not affect interaction with nucleosomes." FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911481" FT MUTAGEN 271 FT /note="K->R: Impaired deubiquitination by USP29. Does not FT affect sumoylation." FT /evidence="ECO:0000269|PubMed:27637147, FT ECO:0000269|PubMed:32457395" FT MUTAGEN 272 FT /note="E->A: Increased DNA-binding activity." FT /evidence="ECO:0000269|PubMed:26829768" FT MUTAGEN 275..278 FT /note="KEIK->AEIA: Does not affect ability to bind FT poly-ADP-ribosylated PARP1." FT /evidence="ECO:0000269|PubMed:35210392" FT MUTAGEN 278 FT /note="K->R: Does not affect ubiquitination by TRIM56." FT /evidence="ECO:0000269|PubMed:29426904" FT MUTAGEN 291 FT /note="S->A: Enhanced stimulation of interferon FT production." FT /evidence="ECO:0000269|PubMed:26440888" FT MUTAGEN 302 FT /note="E->A: Increased nucleotidyltransferase activity." FT /evidence="ECO:0000269|PubMed:26829768" FT MUTAGEN 315 FT /note="K->E: Slightly decreased interaction with FT nucleosomes." FT /evidence="ECO:0000269|PubMed:32911481" FT MUTAGEN 323 FT /note="K->E: Slightly decreased interaction with FT nucleosomes." FT /evidence="ECO:0000269|PubMed:32911481" FT MUTAGEN 335 FT /note="K->E: Decreased DNA-binding and subsequent FT activation. Does not affect nuclear localization and FT tethering to chromatin." FT /evidence="ECO:0000269|PubMed:31808743, FT ECO:0000269|PubMed:32911481" FT MUTAGEN 335 FT /note="K->R: Abolished ubiquitination by TRIM56, leading to FT impaired homodimerization and activation. Does not affect FT sumoylation. Strongly reduced sumoylation; when associated FT with R-372 and R-382." FT /evidence="ECO:0000269|PubMed:27637147, FT ECO:0000269|PubMed:28095500, ECO:0000269|PubMed:29426904" FT MUTAGEN 337 FT /note="R->E: Strongly reduced interaction with FT nucleosomes." FT /evidence="ECO:0000269|PubMed:32911480" FT MUTAGEN 341 FT /note="R->E: Abolished interaction with nucleosomes." FT /evidence="ECO:0000269|PubMed:32911480, FT ECO:0000269|PubMed:32911481" FT MUTAGEN 342 FT /note="R->E: Strongly decreased interaction with FT nucleosomes." FT /evidence="ECO:0000269|PubMed:32911480, FT ECO:0000269|PubMed:32911481" FT MUTAGEN 350 FT /note="K->R: Does not affect ubiquitination by TRIM56." FT /evidence="ECO:0000269|PubMed:29426904" FT MUTAGEN 372 FT /note="K->R: Strongly reduced sumoylation; when associated FT with R-335 and R-382." FT /evidence="ECO:0000269|PubMed:28095500" FT MUTAGEN 382 FT /note="K->A: Decreased DNA-binding and abolished FT homodimerization. Does not affect nuclear localization and FT tethering to chromatin." FT /evidence="ECO:0000269|PubMed:31808743" FT MUTAGEN 382 FT /note="K->E: Slightly decreased interaction with FT nucleosomes." FT /evidence="ECO:0000269|PubMed:32911481" FT MUTAGEN 382 FT /note="K->R: Strongly reduced sumoylation; when associated FT with R-335 and R-372." FT /evidence="ECO:0000269|PubMed:28095500" FT MUTAGEN 386 FT /note="E->A: Abolished homodimerization and subsequent FT activation. Does not affect nuclear localization and FT tethering to chromatin." FT /evidence="ECO:0000269|PubMed:31808743" FT MUTAGEN 395..399 FT /note="KECLK->MECLM: Decreased DNA-binding and subsequent FT activation. Does not affect nuclear localization and FT tethering to chromatin." FT /evidence="ECO:0000269|PubMed:31808743" FT MUTAGEN 399..402 FT /note="KLMK->ALMA: Does not affect ability to bind FT poly-ADP-ribosylated PARP1." FT /evidence="ECO:0000269|PubMed:35210392" FT MUTAGEN 419 FT /note="C->S: Gains susceptibility to mouse-specific RU.521; FT when associated with N-467." FT /evidence="ECO:0000269|PubMed:30007416" FT MUTAGEN 420 FT /note="S->A: Decreased cyclic GMP-AMP synthase activity." FT /evidence="ECO:0000269|PubMed:32474700" FT MUTAGEN 420 FT /note="S->D: Phospho-mimetic mutant; increased cyclic FT GMP-AMP synthase activity." FT /evidence="ECO:0000269|PubMed:32474700" FT MUTAGEN 464 FT /note="K->R: Does not affect deubiquitination by USP29. FT Reduced sumoylation." FT /evidence="ECO:0000269|PubMed:27637147, FT ECO:0000269|PubMed:32457395" FT MUTAGEN 467 FT /note="H->N: Gains susceptibility to mouse-specific RU.521; FT when associated with S-419." FT /evidence="ECO:0000269|PubMed:30007416" FT MUTAGEN 491..497 FT /note="KKIEYER->AKAEYEA: Impaired ability to bind FT poly-ADP-ribosylated PARP1." FT /evidence="ECO:0000269|PubMed:35210392" FT MUTAGEN 491 FT /note="K->R: Abolished monomethylation, promoting FT interaction with PARP1." FT /evidence="ECO:0000269|PubMed:35210392" FT CONFLICT 6 FT /note="R -> I (in Ref. 2; BAE26335)" FT /evidence="ECO:0000305" FT CONFLICT 471 FT /note="P -> R (in Ref. 2; BAE26335)" FT /evidence="ECO:0000305" FT HELIX 150..157 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 161..183 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:5XZG" FT TURN 188..191 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 193..198 FT /evidence="ECO:0007829|PDB:5XZG" FT TURN 199..203 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 207..209 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 211..219 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 222..227 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 229..231 FT /evidence="ECO:0007829|PDB:7JO9" FT STRAND 232..241 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 247..251 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 252..257 FT /evidence="ECO:0007829|PDB:4O6A" FT HELIX 259..275 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 279..284 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 293..314 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 320..322 FT /evidence="ECO:0007829|PDB:5XZG" FT TURN 329..332 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 334..341 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 345..348 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:4K98" FT STRAND 355..358 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 359..361 FT /evidence="ECO:0007829|PDB:4O6A" FT STRAND 363..366 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 368..376 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 379..381 FT /evidence="ECO:0007829|PDB:7BUJ" FT TURN 382..385 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 386..389 FT /evidence="ECO:0007829|PDB:6X59" FT HELIX 394..411 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 413..415 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 420..433 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 437..440 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 442..444 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 445..462 FT /evidence="ECO:0007829|PDB:5XZG" FT STRAND 468..470 FT /evidence="ECO:0007829|PDB:4O6A" FT STRAND 474..476 FT /evidence="ECO:0007829|PDB:7A08" FT TURN 478..480 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 483..498 FT /evidence="ECO:0007829|PDB:5XZG" FT HELIX 502..504 FT /evidence="ECO:0007829|PDB:5XZG" SQ SEQUENCE 507 AA; 58194 MW; 9FDA84DF5E4859CA CRC64; MEDPRRRTTA PRAKKPSAKR APTQPSRTRA HAESCGPQRG ARSRRAERDG DTTEKPRAPG PRVHPARATE LTKDAQPSAM DAAGATARPA VRVPQQQAIL DPELPAVREP QPPADPEARK VVRGPSHRRG ARSTGQPRAP RGSRKEPDKL KKVLDKLRLK RKDISEAAET VNKVVERLLR RMQKRESEFK GVEQLNTGSY YEHVKISAPN EFDVMFKLEV PRIELQEYYE TGAFYLVKFK RIPRGNPLSH FLEGEVLSAT KMLSKFRKII KEEVKEIKDI DVSVEKEKPG SPAVTLLIRN PEEISVDIIL ALESKGSWPI STKEGLPIQG WLGTKVRTNL RREPFYLVPK NAKDGNSFQG ETWRLSFSHT EKYILNNHGI EKTCCESSGA KCCRKECLKL MKYLLEQLKK EFQELDAFCS YHVKTAIFHM WTQDPQDSQW DPRNLSSCFD KLLAFFLECL RTEKLDHYFI PKFNLFSQEL IDRKSKEFLS KKIEYERNNG FPIFDKL //