Preapoptotic Chromatin Condensation Upstream of the Mitochondrial Checkpoint
Bibliographic record
Abstract
When added for a short period (2-4 h) to cells, the kinase inhibitor staurosporine (STS), can trigger double strand breaks, the formation of nuclear foci containing phosphorylated H2AX, Chk2, and p53, a decrease in transcription, and a minor degree of peripheral chromatin condensation. This "preapoptotic chromatin condensation" (PACC) occurs before mitochondrial membrane permeabilization (MMP) and caspase activation become detectable and is not inhibited by Z-VAD-fmk or Bcl-2. PACC is followed by classical apoptosis, when cells are cultured overnight, even when STS is removed from the system. After overnight incubation, STS-pretreated cells manifest mitochondrial cytochrome c release, caspase activation, phosphatidylserine exposure, and apoptotic DNA fragmentation. Caspase or MMP inhibitors did not influence the advent of PACC yet did suppress the evolution of PACC toward apoptosis. Importantly, two unrelated MMP inhibitors (viral mitochondrial inhibitor of apoptosis (vMIA) from cytomegalovirus and mitochondrion-targeted Bcl-2) had a larger range of effects than the pan-caspase inhibitor Z-VAD-fmk. Caspase inhibition simply prevented the transition from PACC to apoptosis yet did not reverse PACC and did not restore transcription. In contrast, Bcl-2 and vMIA allowed for the repair of the DNA lesions, correlating with the reestablishment of active transcription. PACC could also be induced by a gross perturbation of RNA synthesis or primary DNA damage. Again, inhibition of MMP (but not that of caspases) reversed PACC induced by these stimuli. In synthesis, our data reveal the unexpected capacity of STS to induce DNA lesions and suggest qualitative differences in the cytoprotective and DNA repair-inducing potential of different apoptosis inhibitors.
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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) | 0.003 | 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".