The NuA4 acetyltransferase and non-canonical chromatin-associated MRN/ATM activity temporally define senescence-associated secretory programs
Bibliographic record
Abstract
Senescent cells display senescence-associated (SA) phenotypic programs such as proliferation arrest (SAPA) and secretory phenotype (SASP), which mediate their impact on tissue homeostasis. Curiously, senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but SASP requires days to develop, suggesting it requires additional molecular events. Here, we show that pDSBs provoke delayed recruitment of MRN/ATM and KAT5/TRRAP (NuA4/Tip60) complexes to global chromatin. This coincided with activating histone marks on up-regulated SASP genes, whereas depletion of these complexes compromised the SASP. Conversely, histone deacetylase inhibition triggered accelerated MRN/ATM/Tip60-dependent SASP without pDSBs, interlacing acetylation and non-canonical DNA damage-independent, low-level DDR activity in SASP maturation. DDR/acetylation regulation of SA programs is preserved in human cancer cells, suggesting novel targets for modifying treatment-induced SA phenotypes. We propose that delayed chromatin recruitment of acetyltransferases cooperates with non-canonical DDR signaling to ensure SASP activation only in the context of senescence, and not in response to a transient DNA damage-induced proliferation arrest.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".