Modulation of the DNA damage response in UV-exposed human lymphoblastoid cells through genetic-versus functional-inactivation of the p53 tumor suppressor
Bibliographic record
Abstract
The global cellular response to UV-induced DNA damage has been analyzed in the p53-proficient human lymphoblastoid strain TK6 versus two isogenic derivatives wherein p53 activity was abrogated by diverse experimental approaches: (i) NH32, carrying a homozygous genetic knockout of p53; and (ii) TK6-5E, expressing the human papillomavirus E6 oncoprotein which binds and functionally inactivates p53 protein. Although widely employed as such, the extent to which intracellular E6 expression faithfully models the p53 deficient state still remains uncertain. Following irradiation with UV (either monochromatic 254 nm UV or broad-spectrum simulated sunlight), relative to wild-type TK6, p53-null NH32 exhibited virtually identical clonogenic survival and kinetics of G1-S progression but was nonetheless profoundly resistant to apoptosis. In addition, there were significant qualitative and quantitative differences between NH32 and TK6 with respect to UV mutagenesis at the endogenous hypoxanthine phosphoribosyltransferase (hprt) locus. However, important disparities were observed between genetically p53-deficient NH32 and E6-expressing TK6-5E regarding the manner in which they responded to UV-induced genotoxic stress in relation to wild-type TK6. Indeed, although NH32 and TK6-5E behaved similarly with respect to UV mutagenesis at the hprt locus, there were significant differences between these strains in clonogenic survival, apoptosis, and G1-S progression. Using a well-defined isogenic system, our data clearly reveal the influence of p53 inactivation on the global response of human cells to UV-induced DNA damage, and highlight an important caveat in the field of p53 biology by directly demonstrating that this influence varies substantially depending upon whether p53 function is abrogated genetically, or through E6 oncoprotein expression.
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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 | 0.001 |
| 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".