HST2
S. cerevisiae
histone deacetylase HST2
What the model saw
Gene: HST2 Organism: Saccharomyces cerevisiae Known functions: histone deacetylase HST2. NAD binding. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H4K16 deacetylase activity, NAD-dependent. histone deacetylase activity, NAD-dependent. zinc ion binding.
View unredacted entry
histone deacetylase HST2. NAD binding. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H4K16 deacetylase activity, NAD-dependent. histone deacetylase activity, NAD-dependent. zinc ion binding.
Solver output
HST2 is a yeast sirtuin (Sir2 homolog) that uses NAD+ as a cofactor to catalyze NAD-dependent protein lysine deacetylation, directly linking cellular metabolic status to chromatin regulation. Its specific histone H4K16 deacetylase activity maintains a hypoacetylated chromatin state at H4K16, which is associated with transcriptional silencing and genome stability — both hallmarks of youthful cells. Sirtuins as a class are well-established pro-longevity factors in yeast and other organisms, with Sir2 itself being the founding member of lifespan extension via caloric restriction pathways. HST2 in particular has been shown to extend replicative lifespan in yeast, partly by deacetylating histones and non-histone substrates in an NAD+-dependent manner, coupling nutrient sensing to epigenetic maintenance. The NAD+ dependency ties HST2 activity to the deregulated nutrient-sensing/NAMPT-NAD axis, but its primary molecular function is epigenetic (histone deacetylation), placing it squarely in the epigenetic alterations hallmark.
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 correctly predicted pro_longevity for HST2. The mechanistic reasoning is solid: HST2 is indeed a yeast sirtuin with NAD-dependent deacetylase activity, and sirtuins are well-established pro-longevity factors. The model correctly identifies the epigenetic mechanism (H4K16 deacetylation, chromatin silencing) and the NAD+/caloric restriction connection. The reasoning is generally accurate, though the specific claim that "HST2 in particular has been shown to extend replicative lifespan" could be slightly nuanced — HST2's role is somewhat more complex (it can affect both replicative and chronological lifespan), but the overall direction and mechanism are correct. Confidence of 0.72 is appropriate given the complexity.
Raw API responses
solver
{
"reasoning": "HST2 is a yeast sirtuin (Sir2 homolog) that uses NAD+ as a cofactor to catalyze NAD-dependent protein lysine deacetylation, directly linking cellular metabolic status to chromatin regulation. Its specific histone H4K16 deacetylase activity maintains a hypoacetylated chromatin state at H4K16, which is associated with transcriptional silencing and genome stability — both hallmarks of youthful cells. Sirtuins as a class are well-established pro-longevity factors in yeast and other organisms, with Sir2 itself being the founding member of lifespan extension via caloric restriction pathways. HST2 in particular has been shown to extend replicative lifespan in yeast, partly by deacetylating histones and non-histone substrates in an NAD+-dependent manner, coupling nutrient sensing to epigenetic maintenance. The NAD+ dependency ties HST2 activity to the deregulated nutrient-sensing/NAMPT-NAD axis, but its primary molecular function is epigenetic (histone deacetylation), placing it squarely in the epigenetic alterations hallmark.",
"confidence": 0.72,
"key_pathways": [
"NAD+-dependent sirtuin deacetylase signaling",
"Histone H4K16 acetylation/deacetylation chromatin regulation",
"Caloric restriction-linked epigenetic silencing"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for HST2. The mechanistic reasoning is solid: HST2 is indeed a yeast sirtuin with NAD-dependent deacetylase activity, and sirtuins are well-established pro-longevity factors. The model correctly identifies the epigenetic mechanism (H4K16 deacetylation, chromatin silencing) and the NAD+/caloric restriction connection. The reasoning is generally accurate, though the specific claim that \"HST2 in particular has been shown to extend replicative lifespan\" could be slightly nuanced — HST2's role is somewhat more complex (it can affect both replicative and chronological lifespan), but the overall direction and mechanism are correct. Confidence of 0.72 is appropriate given the complexity.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}