Clinical PARP inhibitors allosterically induce PARP2 retention on DNA
Bibliographic record
Abstract
PARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors and contributes to PARP1/2 release from DNA. PARP inhibitors (PARPi) are used in cancer treatment and target PARP1/2 catalytic activity, interfering with repair and increasing PARP1/2 persistence on DNA damage. In addition, certain PARPi exert allosteric effects that increase PARP1 retention on DNA. However, no clinical PARPi exhibit this allosteric behavior toward PARP1. In contrast, we show that certain clinical PARPi exhibit an allosteric effect that retains PARP2 on DNA breaks in a manner that depends on communication between the catalytic and DNA binding regions. Using a PARP2 mutant that mimics an allosteric inhibitor effect, we observed increased PARP2 retention at cellular damage sites. The PARPi AZD5305 also exhibited a clear reverse allosteric effect on PARP2. Our results can help explain the toxicity of clinical PARPi and suggest ways to improve PARPi moving forward.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".