RNH201
S. cerevisiae
ribonuclease H2 catalytic subunit RNH201
What the model saw
Gene: RNH201 Organism: Saccharomyces cerevisiae Known functions: ribonuclease H2 catalytic subunit RNH201. RNA binding. RNA-DNA hybrid ribonuclease activity. nucleic acid binding. protein binding.
View unredacted entry
ribonuclease H2 catalytic subunit RNH201. RNA binding. RNA-DNA hybrid ribonuclease activity. nucleic acid binding. protein binding.
Solver output
RNH201 encodes the catalytic subunit of RNase H2 in S. cerevisiae, which cleaves RNA in RNA-DNA hybrids. Its primary role is the removal of ribonucleotides misincorporated into genomic DNA (ribonucleotide excision repair, RER) and the resolution of R-loops (RNA-DNA hybrids that form co-transcriptionally). Failure to remove embedded ribonucleotides leads to replication fork stalling, DNA strand breaks, and genome instability. Additionally, unresolved R-loops promote transcription-replication conflicts and double-strand break formation. By maintaining genomic integrity through these mechanisms, RNH201 function directly opposes a key hallmark of aging—genomic instability—and its loss is associated with increased mutation rates and DNA damage accumulation. Therefore, the normal function of RNH201 is pro-longevity.
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 about RNH201's role in ribonucleotide excision repair and R-loop resolution is mechanistically plausible in general terms, but it led to the wrong conclusion. In yeast, deletion of RNH201 (rnh201Δ) has been shown to extend chronological or replicative lifespan, making it anti_longevity (its presence shortens life, its absence extends it). The model assumed that because RNH201 maintains genomic integrity, it must be pro-longevity, but the actual experimental data in yeast shows the opposite — loss of RNH201 extends lifespan, possibly through activation of stress response pathways or other compensatory mechanisms. The model was fairly confident (0.72) in its wrong answer, and the mechanistic reasoning, while coherent, did not account for the actual experimental phenotype in yeast aging studies.
Raw API responses
solver
{
"reasoning": "RNH201 encodes the catalytic subunit of RNase H2 in S. cerevisiae, which cleaves RNA in RNA-DNA hybrids. Its primary role is the removal of ribonucleotides misincorporated into genomic DNA (ribonucleotide excision repair, RER) and the resolution of R-loops (RNA-DNA hybrids that form co-transcriptionally). Failure to remove embedded ribonucleotides leads to replication fork stalling, DNA strand breaks, and genome instability. Additionally, unresolved R-loops promote transcription-replication conflicts and double-strand break formation. By maintaining genomic integrity through these mechanisms, RNH201 function directly opposes a key hallmark of aging—genomic instability—and its loss is associated with increased mutation rates and DNA damage accumulation. Therefore, the normal function of RNH201 is pro-longevity.",
"confidence": 0.72,
"key_pathways": [
"ribonucleotide excision repair (RER)",
"R-loop resolution",
"DNA replication fidelity"
],
"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 about RNH201's role in ribonucleotide excision repair and R-loop resolution is mechanistically plausible in general terms, but it led to the wrong conclusion. In yeast, deletion of RNH201 (rnh201Δ) has been shown to extend chronological or replicative lifespan, making it anti_longevity (its presence shortens life, its absence extends it). The model assumed that because RNH201 maintains genomic integrity, it must be pro-longevity, but the actual experimental data in yeast shows the opposite — loss of RNH201 extends lifespan, possibly through activation of stress response pathways or other compensatory mechanisms. The model was fairly confident (0.72) in its wrong answer, and the mechanistic reasoning, while coherent, did not account for the actual experimental phenotype in yeast aging studies.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}