A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging.
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Naked mole-rat cGAS has lost the homologous-recombination-suppressing activity of its human and mouse orthologs, through four amino acid changes fixed during evolution.
"naked mole-rat cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution"
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The mechanism is prolonged chromatin retention after DNA damage, caused by weakened TRIM41-mediated ubiquitination and weakened p97 engagement.
"The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97."
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Chromatin-retained cGAS promotes the FANCI-RAD50 interaction and RAD50 recruitment to damage sites, potentiating homologous recombination repair.
"Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair."
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The same four residues mediate an anti-ageing and lifespan-extending function.
"Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span."
Longevity steps on the cGAS.
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Science commentary on the primary study, framing the naked-mole-rat cGAS DNA-repair activity as a candidate longevity mechanism and still describing cGAS as a cytosolic sensor.
"A DNA repair function in a cytosolic sensor demonstrates a potential role in naked mole-rat longevity."
The naked mole-rat cGAS promotes homologous recombination repair and delays aging.
Naked mole rat cGAS sticks it out.
Genome Stability Maintenance in Naked Mole-Rat.
DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat.
TreeGrafter-generated GO annotations
Focused OpenScientist report on HETGA Cgas dsRNA versus dsDNA response
Naked mole-rat cGAS (A0AAX6RS70): conservation of catalytic and chromatin-binding residues
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The catalytic triad, zinc-coordinating residues and nucleosome anchor are retained. Most nucleotide contacts are conserved, with a documented human T211-to-target A243 substitution; there is no pseudoenzyme signature.
"Every catalytically important residue that UniProt annotates on human cGAS is present and identical in the naked mole-rat protein"
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The four residues that differ and reverse the HR phenotype lie in the C-terminal regulatory domain, well away from the active site.
"All four positions fall inside the C-terminal Mab-21-like HhH/H2TH-like domain that UniProt annotates at 437-541 on A0AAX6RS70."
Functional Annotation Report: *Heterocephalus glaber Mb21d1* / cGAS
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The nuclear, nucleosome-tethered pool is the dominant resting pool of mammalian cGAS, not a minor one.
"A 2024 authoritative review reports that nuclear cGAS can constitute approximately **85–95%** of total cGAS in some cell types."
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Nucleosome tethering actively restrains cGAS: it occludes the DNA-binding and oligomerization surfaces, and breaking the tether at the arginine anchor causes massive constitutive cGAMP production.
"mouse R241E generated about **300-fold** more basal cGAMP than wild type, and human R255E generated over **100-fold** more"
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The report's own literature search returned no naked-mole-rat-specific functional study of this protein — a conclusion contradicted by PMID:41066557, which the search missed.
"There is no verified naked-mole-rat kinetic constant, catalytic rate, DNA-length response curve, product measurement, structure, tissue-expression map, or subcellular localization for this accession."
Affinage mechanistic annotation for CGAS (human)
Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.
Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.
The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the DNA size restriction of core-cGAS activity.
Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation.
Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity.