SIR2
S. cerevisiae
NAD-dependent histone deacetylase SIR2
What the model saw
Gene: SIR2 Organism: Saccharomyces cerevisiae Known functions: NAD-dependent histone deacetylase SIR2. DNA replication origin binding. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H3K14 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H4K16 deacetylase activity, NAD-dependent. histone deacetylase activity, NAD-dependent. nucleosome binding. protein binding. transcription corepressor activity. zinc ion binding.
View unredacted entry
NAD-dependent histone deacetylase SIR2. DNA replication origin binding. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H3K14 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H4K16 deacetylase activity, NAD-dependent. histone deacetylase activity, NAD-dependent. nucleosome binding. protein binding. transcription corepressor activity. zinc ion binding.
Solver output
SIR2 encodes the founding member of the sirtuin family of NAD+-dependent histone deacetylases in S. cerevisiae. Its deacetylation of histone H4K16, H3K9, and H3K14 promotes chromatin silencing at telomeres, rDNA loci, and mating-type loci, directly suppressing the accumulation of extrachromosomal rDNA circles (ERCs), a primary driver of yeast replicative aging. SIR2 activity is coupled to cellular NAD+ levels, linking metabolic status to epigenetic regulation and nutrient-sensing pathways. Overexpression of SIR2 extends replicative lifespan in yeast, while deletion shortens it, establishing it as a canonical pro-longevity gene. Its transcription corepressor activity and nucleosome binding further reinforce heterochromatin maintenance, preventing age-associated epigenetic drift and genomic instability at repetitive loci.
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 "pro_longevity" with very high confidence (0.97), but the ground truth is "unclear." The mechanistic reasoning is largely accurate — SIR2 is indeed a well-known NAD+-dependent histone deacetylase involved in rDNA silencing and ERC suppression, and overexpression has been reported to extend replicative lifespan. However, the picture is more complicated: subsequent research has shown that SIR2's lifespan extension effects are context-dependent and sometimes disputed (e.g., effects depend on genetic background, caloric restriction interactions, and some studies show no lifespan extension or even negative effects under certain conditions). The GenAge database classifies it as "unclear," reflecting this scientific controversy. The model's overconfidence (0.97) in a "pro_longevity" classification is the key failure — it presents the classic textbook narrative without acknowledging the substantial contradictory evidence that led GenAge to classify it as unclear.
Raw API responses
solver
{
"reasoning": "SIR2 encodes the founding member of the sirtuin family of NAD+-dependent histone deacetylases in S. cerevisiae. Its deacetylation of histone H4K16, H3K9, and H3K14 promotes chromatin silencing at telomeres, rDNA loci, and mating-type loci, directly suppressing the accumulation of extrachromosomal rDNA circles (ERCs), a primary driver of yeast replicative aging. SIR2 activity is coupled to cellular NAD+ levels, linking metabolic status to epigenetic regulation and nutrient-sensing pathways. Overexpression of SIR2 extends replicative lifespan in yeast, while deletion shortens it, establishing it as a canonical pro-longevity gene. Its transcription corepressor activity and nucleosome binding further reinforce heterochromatin maintenance, preventing age-associated epigenetic drift and genomic instability at repetitive loci.",
"confidence": 0.97,
"key_pathways": [
"NAD+-dependent chromatin silencing / rDNA stability",
"Sirtuin-mediated histone deacetylation (H4K16ac, H3K9ac, H3K14ac)",
"Nutrient sensing via NAD+/NADH ratio coupling"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" with very high confidence (0.97), but the ground truth is \"unclear.\" The mechanistic reasoning is largely accurate — SIR2 is indeed a well-known NAD+-dependent histone deacetylase involved in rDNA silencing and ERC suppression, and overexpression has been reported to extend replicative lifespan. However, the picture is more complicated: subsequent research has shown that SIR2's lifespan extension effects are context-dependent and sometimes disputed (e.g., effects depend on genetic background, caloric restriction interactions, and some studies show no lifespan extension or even negative effects under certain conditions). The GenAge database classifies it as \"unclear,\" reflecting this scientific controversy. The model's overconfidence (0.97) in a \"pro_longevity\" classification is the key failure — it presents the classic textbook narrative without acknowledging the substantial contradictory evidence that led GenAge to classify it as unclear.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": true
}