The retinoblastoma protein and PML collaborate to organize heterochromatin and silence E2F-responsive genes during senescence
Bibliographic record
Abstract
Cellular senescence is characterized by silencing of genes involved in DNA replication and cell cycle progression. Stable repression is crucial for preventing inappropriate DNA synthesis and the maintenance of a prolonged senescent state. Many of these genes are targets for E2F transcription factors. The pRB pathway plays a major role in senescence by directly repressing E2Fs and also by regulating chromatin at the promoters of E2F target genes using its LXCXE cleft-dependent interactions. In this study, we sought to investigate the mechanisms by which pRB stably silences E2F target gene transcription during cellular senescence. We report that in mouse embryonic fibroblasts, endogenous promyelocytic leukemia protein (PML) associates with E2F target genes in a pRB LXCXE-dependent manner during HrasV12-induced senescence. Furthermore, using a PML-IV-induced senescence model, we show that the pRB LXCXE binding cleft is essential for PML association with gene promoters, silencing of E2F target genes, and stable cell cycle exit. Binding assays show that pRB can interact with PML specifically during senescence, suggesting that signaling events in senescence regulate assembly of PML and pRB to establish heterochromatin and create a permanent cell cycle arrest.
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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 | 0.000 | 0.000 |
| 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".