NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake.
Bibliographic record
Abstract
The platinum-based drugs cis- and carboplatin, which are crucial for treating cancers with DNA repair defects, like those caused by BRCA1/2 mutations, rely on the volume-regulated anion channel subunits LRRC8A and LRRC8D for about 50% of cellular drug uptake. Yet, the precise mechanisms of how LRRC8A and LRRC8D mediate this function are largely unknown. Here, we identify NAA60, an N-terminal acetyltransferase, which localizes to the Golgi apparatus to affect LRRC8A and LRRC8D function. Our data suggest that NAA60 acetylates the LRRC8A/D N-termini, and its loss decreases cis- and carboplatin uptake resulting in drug resistance of otherwise hypersensitive BRCA1;p53-deficient cells and tumors. Furthermore, we mimicked the absence of the neutralizing acetyl moiety that is observed after loss of NAA60 by introducing positively charged amino acids at the N-termini of LRRC8A/D, which indeed decreased cis- and carboplatin sensitivity. Our findings highlight the importance of N-terminal acetylation by NAA60 for effective platinum drug uptake, offering new insights into overcoming drug resistance.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| 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".