RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes
Bibliographic record
Abstract
Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma (RARG) gene is associated with increased susceptibility to DIC, but the precise mechanism underlying this association is incompletely understood. We performed molecular dynamic simulations to determine the effect of this variant on RARG structure and then validated these predictions using CRISPR-Cas9-genome-edited, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We found that this variant leads to reduced activation of its target genes in response to doxorubicin, including gene pathways involved in DNA repair and consequently an inability to mediate DNA repair after exposure to doxorubicin. Our findings establish a role of RARG p.S427L in attenuating DNA repair in DIC and provide insight into the pathogenesis of this cardiotoxic effect.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".