CGAS (Cyclic GMP-AMP synthase) — curation notes

UniProt: Q8N884 | HGNC: CGAS (HGNC:21367) | synonyms: C6orf150, MB21D1 | EC 2.7.7.86
Family: mab-21 family / cGAS-DncV-like nucleotidyltransferase (cGLR); OAS1-like NTase + Mab21 domain.

Provenance note: just deep-research was attempted with --provider perplexity (not
configured; only falcon and openscientist available) and then --provider falcon.
Findings below are drawn from the cached UniProt record and cached publications/PMID_*.md
full texts/abstracts, with inline provenance. No -deep-research-<provider>.md file was
fabricated.

Core molecular function

cGAS is a cytosolic double-stranded DNA sensor and a DNA-activated nucleotidyltransferase
that catalyzes synthesis of the cyclic dinucleotide second messenger 2',3'-cGAMP from ATP
and GTP.

• Discovery / cGAMP synthase activity: cGAS was purified as the cGAMP synthase; "cGAS bound
  to DNA in the cytoplasm and catalyzed cGAMP synthesis" and "purified cGAS catalyzes the
  synthesis of cGAMP from ATP and GTP" PMID:23258413.
  The synthesis requires both ATP and GTP and is DNA-dependent PMID:23258413.
• The product is specifically 2',3'-cGAMP with mixed 2'-5'/3'-5' linkages: 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]"
  (UniProt FUNCTION; structural basis in PMID:38740774 and PMID:28214358).
• 2',3'-cGAMP is the endogenous second messenger [PMID:23258412 second-messenger paper];
  the noncanonical 2',3' linkage is the universal metazoan signal PMID:26300263.
• EC 2.7.7.86; RHEA:42064. Many independent EXP/IDA confirmations (PMID:23707061, 23722159,
  25131990, 28934246, 29976794, 30799039, 31142647, 32814054, 37802025, and others).

DNA binding / activation mechanism

• Directly binds dsDNA in a sequence-independent, length-dependent manner; the catalytic
  domain + N-terminal disordered region both contribute [PMID:23258413; PMID:28363908].
• DNA binding drives liquid-liquid phase separation (LLPS): "DNA binding to cGAS robustly
  induced the formation of liquidlike droplets in which cGAS was activated" and "The
  disordered and positively charged cGAS N terminus enhanced cGAS-DNA phase separation by
  increasing the valencies of DNA binding" PMID:29976794. These DNA-cGAS condensates are
  the sites of activation → basis of GO:0140693 molecular condensate scaffold activity
  (also PMID:32911482, 32912999, 35322803, 38421872, 38740774, 39322678).
• Forms a 2:2 dimer with dsDNA (structural: PMID:30007416, 30799039, 31142647).
• Human cGAS preferentially recognizes curved long dsDNA (>~40 bp) via K187/L195 substitutions
  [UniProt DOMAIN; PMID:30007416].

Downstream pathway (cGAS/STING)

• cGAMP binds and activates STING1 (TMEM173), triggering TBK1/IRF3 and type I interferon
  (IFN-beta) production: "cGAS functions upstream of STING and is required for IFNβ induction
  by cytosolic DNA" PMID:23258413. This is the cGAS/STING signaling pathway (GO:0140896) and
  positive regulation of type I interferon production (GO:0032481).
• Defense against DNA viruses (HSV-1, vaccinia) PMID:23258413 and retroviruses (HIV-2;
  HIV-1 poorly sensed due to capsid cloaking) [PMID:23929945; PMID:26046437 PQBP1 co-sensor].
• Paracrine/bystander spread: "cGAMP(2'-5') is transferred from producing cells to
  neighbouring cells through gap junctions, where it promotes STING activation" PMID:24077100
  → basis of GO:0038001 paracrine signaling.

Sensing endogenous/self DNA and sterile inflammation

• Surveys micronuclei from genome instability: "cGAS localizes to micronuclei arising from
  genome instability" PMID:28738408; links genome instability/DNA damage to innate immunity.
• Cellular senescence (SASP via cytoplasmic chromatin fragments) — mouse ISS (GO:2000774).
• Sensed in autoinflammatory disease from defective histone pre-mRNA processing PMID:33230297.

Nuclear cGAS, chromatin/nucleosome inhibition, and DNA-repair suppression

• cGAS is predominantly nuclear at steady state and tightly tethered to chromatin to prevent
  autoreactivity [PMID:31808743; PMID:32792394 BAF]; localizes to nucleus (many EXP: PMID:29263269,
  30270045, 30811988, 31299200, 31808743, 33476576, 34111399, 35438208) and chromosomes/centromeres
  (PMID:30811988, 31299200, 31544964, 32351706, 32912999, 33051594).
• Nucleosome binding inactivates cGAS: cGAS binds the histone H2A-H2B acidic patch via an
  arginine anchor, blocking DNA binding/activation — structural basis established by multiple
  cryo-EM studies [PMID:32911482; PMID:32912999 "two cGAS monomers bridge two NCPs by binding
  the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA"; PMID:33051594]. This is
  the mechanism of GO:0031491 nucleosome binding and (uninformatively) chromatin binding.
• Enzyme-independent nuclear moonlighting function: nuclear cGAS suppresses homologous
  recombination and promotes tumorigenesis: "Here we demonstrate that cGAS inhibits homologous
  recombination in mouse and human models" PMID:30356214; "cGAS is a chromatin-bound protein
  that restrains HR and that this function is independent of its enzymatic activity or the
  canonical STING-IFN-I pathway" PMID:31544964. It interacts with PARP1 and impedes the
  PARP1-TIMELESS complex PMID:30356214. → GO:2000042 (neg reg of DSB repair via HR),
  GO:0045738 (neg reg of DNA repair, mouse IEA), and it localizes to sites of DSB (GO:0035861).

Regulation / interactors (context; mostly not core function terms)

• Positive: ZCCHC3 co-sensor PMID:30135424; PQBP1 (HIV sensing) PMID:26046437; G3BP1 promotes
  DNA binding PMID:30510222; TRIM56 monoUb K347 PMID:29426904; KAT5 acetylation PMID:32817552;
  HERC5 ISGylation PMID:38421872; MYO1F positions cGAS at plasma membrane PMID:39694035.
• Negative: nucleosomes; PCBP2 antagonizes condensation PMID:35322803; PARP1 PARylation
  PMID:35460603; acetylation blocks activity PMID:30799039; PRMT5 methylation PMID:33762328;
  CDK1 phosphorylation in mitosis [PMID:32351706, 33542149]; CRL5-SPSB3 degradation PMID:38418882;
  AARS1/2 lactylation PMID:39322678; LYPLAL1 depalmitoylation PMID:37802025.
• PIP2/PI(4,5)P2 binding positions cGAS at plasma membrane PMID:30827685 → GO:0005546.
• Metal/cofactor: Mn2+ directly activates cGAS PMID:32814054; Zn2+ enhances activity PMID:29976794.

Localization summary

Nucleus (predominant, chromatin-tethered), cytosol (activation upon dsDNA), plasma membrane
(peripheral, PIP2/MYO1F-dependent). Cytosol is where cGAS carries out active DNA sensing;
nucleus is where it is largely sequestered/inactivated and performs its enzyme-independent
DNA-repair-suppressing moonlighting role.

Core-function conclusions (for core_functions block)

1. Double-stranded DNA binding (GO:0003690) — the sensing/input activity.
2. 2',3'-cyclic GMP-AMP synthase activity (GO:0061501) — the catalytic output.
3. Molecular condensate scaffold activity (GO:0140693) — DNA-driven LLPS platform for activation.
4. Process: cGAS/STING signaling pathway (GO:0140896) / activation of innate immune response.

Notable non-core but real: nucleosome binding (inhibitory regulatory), negative regulation of
DSB repair via HR (enzyme-independent nuclear moonlighting), positive regulation of cellular
senescence, paracrine signaling.