Abstract 3916: PML nuclear bodies are juxtaposed to DNA-DSBs following IR-induced DNA damage
Bibliographic record
Abstract
Abstract The promyelocytic leukemia (PML) tumor suppressor protein aggregates in discrete PML nuclear bodies (PML-NBs) that are detectable by immunofluorescent microscopy. PML-NB number can change in response to cell cycle and various cell stresses, including DNA damage. Intra-nuclear γH2AX foci form following ionizing radiation (IR) as a function of dose and time and are used as an indicator of DNA double strand breaks (DNA-DSBs). However, whether PML-NBs are associated with exogenous or endogenous (e.g. DNA replication associated) damage was unclear. Using G0-G1 synchronized human fibroblast (GM05757) to exclude endogenous DNA damage, we examined the intra-nuclear locales of γH2AX and other DNA repair biomarkers with respect to PML-NBs following IR. PML +/+ and -/- MEFs did not vary in DNA-DSB repair based on comet assay. Consistent with this, PML-NBs did not respond to immediate DNA damage. However, 3D-confocal microscopy studies showed that PML-NBs associated with the majority of residual γH2AX sites at later times (24h post-IR). Using quantitative microscopy, these associations were distinguishable as juxtaposition and not true co-localization (i.e., between γH2AX and DSB marker 53BP1). Continued presence of damage sensing and signaling proteins (MRE11, NBS1, MDC1 and 53BP1) and persistent kinase activity (DNA-PK, ATM, CHK2) was observed at these residual γH2AX sites. Absence of RAD51 and BRCA1 indicated that these were not replication-associated breaks and the exclusion of TRF2 suggested that these were not telomeric regions; rather PML-NBs associated specifically with unrepaired exogenous DSBs. Residual γH2AX sites were not enriched in eu- or heterochromatin. Interestingly, scanning electron imaging revealed a lower chromatin density near residual γH2AX foci, suggesting chromatin remodeling in the vicinity of unrepaired breaks. Live cell experiment using GFP-PML IV and mCherry-53BP1tudor domain suggested that PML-NB mobility facilitated the association with residual 53BP1 foci. Our data suggests that maintenance of genomic stability may depend, in part, on the association between PML-NBs and residual γH2AX foci. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2011-3916
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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 | 0.001 | 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 | 0.001 | 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".