VPS75
S. cerevisiae
Vps75p
What the model saw
Gene: VPS75 Organism: Saccharomyces cerevisiae Known functions: Vps75p. H3-H4 histone complex chaperone activity. acetyltransferase activator activity. chromatin binding. histone binding. identical protein binding. protein binding.
View unredacted entry
Vps75p. H3-H4 histone complex chaperone activity. acetyltransferase activator activity. chromatin binding. histone binding. identical protein binding. protein binding.
Solver output
VPS75 encodes a histone H3-H4 chaperone that partners with the Rtt109 acetyltransferase to promote H3K56 acetylation, a mark critical for chromatin reassembly after DNA replication and repair. By acting as an acetyltransferase activator (stimulating Rtt109), VPS75 facilitates proper histone deposition and maintenance of chromatin integrity. Loss of H3K56ac is associated with genomic instability and impaired DNA damage responses, both of which accelerate aging in yeast. Proper histone chaperoning by VPS75 also helps preserve epigenetic information encoded in nucleosome positioning and histone modification patterns, counteracting age-associated epigenetic drift. Thus, VPS75's normal function supports chromatin homeostasis and epigenetic fidelity, which are pro-longevity activities in S. cerevisiae.
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 but the ground truth is anti_longevity. The model's mechanistic reasoning is plausible on its face — VPS75 does partner with Rtt109 to promote H3K56 acetylation, and this pathway is involved in DNA damage response and chromatin integrity. However, the model drew the wrong conclusion about the direction of effect. In yeast, deletion of VPS75 actually extends lifespan, making it anti_longevity (its normal function shortens lifespan). The model's logic assumed that because VPS75 supports chromatin homeostasis, it must be pro-longevity, but failed to consider that VPS75/Rtt109-mediated H3K56ac and histone chaperoning activity may actually promote aging processes (e.g., through effects on replication-coupled chromatin assembly that accelerate replicative aging). The model had moderate confidence (0.62) but was still wrong on both the answer and the mechanistic interpretation of the direction of effect.
Raw API responses
solver
{
"reasoning": "VPS75 encodes a histone H3-H4 chaperone that partners with the Rtt109 acetyltransferase to promote H3K56 acetylation, a mark critical for chromatin reassembly after DNA replication and repair. By acting as an acetyltransferase activator (stimulating Rtt109), VPS75 facilitates proper histone deposition and maintenance of chromatin integrity. Loss of H3K56ac is associated with genomic instability and impaired DNA damage responses, both of which accelerate aging in yeast. Proper histone chaperoning by VPS75 also helps preserve epigenetic information encoded in nucleosome positioning and histone modification patterns, counteracting age-associated epigenetic drift. Thus, VPS75's normal function supports chromatin homeostasis and epigenetic fidelity, which are pro-longevity activities in S. cerevisiae.",
"confidence": 0.62,
"key_pathways": [
"H3K56 acetylation via Rtt109-VPS75 complex",
"histone H3-H4 chaperoning and chromatin reassembly",
"DNA damage response and chromatin integrity maintenance"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's mechanistic reasoning is plausible on its face — VPS75 does partner with Rtt109 to promote H3K56 acetylation, and this pathway is involved in DNA damage response and chromatin integrity. However, the model drew the wrong conclusion about the direction of effect. In yeast, deletion of VPS75 actually extends lifespan, making it anti_longevity (its normal function shortens lifespan). The model's logic assumed that because VPS75 supports chromatin homeostasis, it must be pro-longevity, but failed to consider that VPS75/Rtt109-mediated H3K56ac and histone chaperoning activity may actually promote aging processes (e.g., through effects on replication-coupled chromatin assembly that accelerate replicative aging). The model had moderate confidence (0.62) but was still wrong on both the answer and the mechanistic interpretation of the direction of effect.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}