GCN4
S. cerevisiae
amino acid starvation-responsive transcription factor GCN4
What the model saw
Gene: GCN4 Organism: Saccharomyces cerevisiae Known functions: amino acid starvation-responsive transcription factor GCN4. DNA-binding transcription activator activity, RNA polymerase II-specific. DNA-binding transcription factor activity. DNA-binding transcription factor activity, RNA polymerase II-specific. RNA polymerase II cis-regulatory region sequence-specific DNA binding. RNA polymerase II-specific DNA-binding transcription factor binding. TFIID-class transcription factor complex binding. chromatin binding. identical protein binding. mediator complex binding. protein binding. sequence-specific DNA binding.
View unredacted entry
amino acid starvation-responsive transcription factor GCN4. DNA-binding transcription activator activity, RNA polymerase II-specific. DNA-binding transcription factor activity. DNA-binding transcription factor activity, RNA polymerase II-specific. RNA polymerase II cis-regulatory region sequence-specific DNA binding. RNA polymerase II-specific DNA-binding transcription factor binding. TFIID-class transcription factor complex binding. chromatin binding. identical protein binding. mediator complex binding. protein binding. sequence-specific DNA binding.
Solver output
GCN4 is the master transcriptional activator of the integrated stress response (ISR) in yeast, activated specifically under amino acid starvation conditions via the GCN2-eIF2α kinase pathway. When amino acids are limiting, GCN2 phosphorylates eIF2α, paradoxically increasing GCN4 translation, which then upregulates genes for amino acid biosynthesis, autophagy, and stress resistance. This pathway is functionally analogous to the mammalian ATF4/ISR axis and intersects directly with TOR (TORC1) nutrient-sensing signaling — conditions that activate GCN4 (amino acid deprivation, reduced TORC1 activity) are well-established pro-longevity interventions in yeast. GCN4 overexpression or constitutive activation has been shown to extend chronological and replicative lifespan in S. cerevisiae by mimicking dietary restriction signals and upregulating protective stress-response programs. Its binding to the Mediator complex and TFIID further positions it as a broad transcriptional coordinator of the nutrient-deprivation longevity response.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted GCN4 as pro_longevity with 0.78 confidence, but the ground truth is anti_longevity. The model's reasoning about GCN4's role in the integrated stress response and its connection to TOR/nutrient sensing is partially accurate mechanistically (GCN4 is indeed activated under amino acid starvation via GCN2-eIF2α), but the conclusion about its longevity effect is wrong. In reality, GCN4 is anti-longevity in yeast — its activation can shorten lifespan, likely because sustained GCN4 activity imposes metabolic costs or because GCN4 promotes processes that are detrimental when chronically activated. The model's claim that "GCN4 overexpression or constitutive activation has been shown to extend chronological and replicative lifespan" appears to be a hallucinated or incorrect citation of the literature, as the GenAge database classifies it as anti_longevity. The model conflated the pro-longevity nature of the upstream pathway (amino acid deprivation, reduced TORC1) with the downstream effector GCN4 itself having a pro-longevity role, which is incorrect.
Raw API responses
solver
{
"reasoning": "GCN4 is the master transcriptional activator of the integrated stress response (ISR) in yeast, activated specifically under amino acid starvation conditions via the GCN2-eIF2α kinase pathway. When amino acids are limiting, GCN2 phosphorylates eIF2α, paradoxically increasing GCN4 translation, which then upregulates genes for amino acid biosynthesis, autophagy, and stress resistance. This pathway is functionally analogous to the mammalian ATF4/ISR axis and intersects directly with TOR (TORC1) nutrient-sensing signaling — conditions that activate GCN4 (amino acid deprivation, reduced TORC1 activity) are well-established pro-longevity interventions in yeast. GCN4 overexpression or constitutive activation has been shown to extend chronological and replicative lifespan in S. cerevisiae by mimicking dietary restriction signals and upregulating protective stress-response programs. Its binding to the Mediator complex and TFIID further positions it as a broad transcriptional coordinator of the nutrient-deprivation longevity response.",
"confidence": 0.78,
"key_pathways": [
"GCN2-eIF2α-GCN4 integrated stress response",
"TOR/nutrient-sensing pathway (dietary restriction mimicry)",
"Amino acid biosynthesis and autophagy transcriptional program"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted GCN4 as pro_longevity with 0.78 confidence, but the ground truth is anti_longevity. The model's reasoning about GCN4's role in the integrated stress response and its connection to TOR/nutrient sensing is partially accurate mechanistically (GCN4 is indeed activated under amino acid starvation via GCN2-eIF2α), but the conclusion about its longevity effect is wrong. In reality, GCN4 is anti-longevity in yeast — its activation can shorten lifespan, likely because sustained GCN4 activity imposes metabolic costs or because GCN4 promotes processes that are detrimental when chronically activated. The model's claim that \"GCN4 overexpression or constitutive activation has been shown to extend chronological and replicative lifespan\" appears to be a hallucinated or incorrect citation of the literature, as the GenAge database classifies it as anti_longevity. The model conflated the pro-longevity nature of the upstream pathway (amino acid deprivation, reduced TORC1) with the downstream effector GCN4 itself having a pro-longevity role, which is incorrect.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}