parp-1
C. elegans
Poly
What the model saw
Gene: parp-1 Organism: Caenorhabditis elegans Known functions: Poly. DNA binding. NAD binding. NAD+ poly-ADP-ribosyltransferase activity. NAD+-protein-aspartate ADP-ribosyltransferase activity. NAD+-protein-glutamate ADP-ribosyltransferase activity. zinc ion binding.
View unredacted entry
Poly. DNA binding. NAD binding. NAD+ poly-ADP-ribosyltransferase activity. NAD+-protein-aspartate ADP-ribosyltransferase activity. NAD+-protein-glutamate ADP-ribosyltransferase activity. zinc ion binding.
Solver output
PARP-1 (Poly(ADP-ribose) polymerase-1) is a DNA damage sensor that binds DNA strand breaks and catalyzes poly-ADP-ribosylation of target proteins (on aspartate and glutamate residues), recruiting and activating the DNA damage response and repair machinery. By facilitating efficient DNA repair, PARP-1 normally suppresses genomic instability, a primary hallmark of aging. However, PARP-1 activity is a major consumer of NAD+, and excessive or chronic PARP-1 activation can deplete cellular NAD+ pools, which would secondarily impair sirtuin activity and mitochondrial function — a known pro-aging effect. In C. elegans, studies generally support that basal PARP activity contributes to genome maintenance and correlates positively with longevity across species, consistent with the "longevity assurance" role of DNA repair. The zinc-finger domain mediates DNA binding for damage detection, and NAD+ binding is essential for the ADP-ribosylation catalytic cycle that signals repair. On balance, the primary function of maintaining genomic integrity places parp-1 in a pro-longevity role, though the NAD+ consumption trade-off introduces some uncertainty.
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 reasoning focused on PARP-1's role in DNA repair as a longevity-promoting mechanism, while acknowledging the NAD+ depletion trade-off but dismissing it. In C. elegans, parp-1 is actually anti-longevity, meaning its loss or inhibition extends lifespan — likely because PARP-1 activity depletes NAD+ pools, impairing sirtuins and other NAD+-dependent processes. The model identified the NAD+ depletion mechanism as a possibility but incorrectly weighted the DNA repair function as dominant. The mechanistic reasoning was partially correct in identifying the relevant pathways but drew the wrong conclusion about the net effect on longevity. Confidence was 0.62, which is moderately confident in the wrong direction.
Raw API responses
solver
{
"reasoning": "PARP-1 (Poly(ADP-ribose) polymerase-1) is a DNA damage sensor that binds DNA strand breaks and catalyzes poly-ADP-ribosylation of target proteins (on aspartate and glutamate residues), recruiting and activating the DNA damage response and repair machinery. By facilitating efficient DNA repair, PARP-1 normally suppresses genomic instability, a primary hallmark of aging. However, PARP-1 activity is a major consumer of NAD+, and excessive or chronic PARP-1 activation can deplete cellular NAD+ pools, which would secondarily impair sirtuin activity and mitochondrial function — a known pro-aging effect. In C. elegans, studies generally support that basal PARP activity contributes to genome maintenance and correlates positively with longevity across species, consistent with the \"longevity assurance\" role of DNA repair. The zinc-finger domain mediates DNA binding for damage detection, and NAD+ binding is essential for the ADP-ribosylation catalytic cycle that signals repair. On balance, the primary function of maintaining genomic integrity places parp-1 in a pro-longevity role, though the NAD+ consumption trade-off introduces some uncertainty.",
"confidence": 0.62,
"key_pathways": [
"DNA damage response and base excision repair",
"Poly-ADP-ribosylation signaling",
"NAD+ metabolism"
],
"mechanism_class": "genomic_instability",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning focused on PARP-1's role in DNA repair as a longevity-promoting mechanism, while acknowledging the NAD+ depletion trade-off but dismissing it. In C. elegans, parp-1 is actually anti-longevity, meaning its loss or inhibition extends lifespan — likely because PARP-1 activity depletes NAD+ pools, impairing sirtuins and other NAD+-dependent processes. The model identified the NAD+ depletion mechanism as a possibility but incorrectly weighted the DNA repair function as dominant. The mechanistic reasoning was partially correct in identifying the relevant pathways but drew the wrong conclusion about the net effect on longevity. Confidence was 0.62, which is moderately confident in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}