PML nuclear bodies are juxtaposed to DNA-DSBs following IR-induced DNA damage
Bibliographic record
Abstract
4317 The promyelocytic leukemia (PML) tumor suppressor protein aggregates in discrete PML nuclear bodies (PML-NBs) that are detectable by immunofluorescenct microscopy. PML foci number can change as a function of the cell cycle and various cell stresses, including DNA damage. γ-H2AX nuclear foci are commonly used as an indicator of DNA double strand breaks (DNA-DSBs). γ-H2AX foci increase in response to DNA-DSBs in a time- and dose-responsive fashion and resolve to background level upon the repair of DNA-DSBs. Our labs have previously published (Dellaire et al., JCB, 2006) the post-irradiation kinetics of γ-H2AX and PML foci in asynchronous cell populations. In the minutes following DNA damage, PML foci increased in number especially in S-phase cells. However, whether PML-NBs were associated with exogenous or endogenous (e.g. DNA replication associated) damage was unclear. In a detailed study, we have determined the number and intra-nuclear locale of γ-H2AX and other DNA repair biomarkers (e.g. 53BP1, RAD51, RPA, MRE11, TRF2 and MDC1) in relation to PML foci, within G0-G1 synchronized normal human fibroblasts (GM5757) to solely characterize PML responses to exogenous DNA damage. Following a clinically-relevant dose of 2Gy, PML foci number remained constant over 24 hours in contrast to initial induction and resolution kinetics of the known DNA-DSB biomarkers. In other studies, PML foci number was independent of radiation dose and in contrast to γ-H2AX and 53BP1, did not show increased residual foci at 24 hours in 180BR (NHEJ-deficient) cells or following DNA-PKcs biochemical inhibition with KU-7440. However, 3-D confocal microscopy studies showed that PML bodies juxtaposed to the sites of γ-H2AX-associated DNA-DSBs suggesting involvement in unique chromatin-based locales of DNA repair. Ongoing experiments are testing whether this juxtaposition is in euchromatin or heterochromatin and whether S-phase cells differ in this PML-associated biology. The effect of hypoxia is also being investigated on PML/DNA-DSB juxtaposition and will be reported. Our studies support that PML-NBs are juxtaposed with DNA-DSBs following both exogenous and endogenous DNA damage and may be preferential intranuclear sites of DNA repair.
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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 | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".