A Majority of Human Melanoma Cell Lines Exhibits an S Phase-Specific Defect in Excision of UV-Induced DNA Photoproducts
Bibliographic record
Abstract
It is well established that efficient removal of highly-promutagenic UV-induced dipyrimidine photoproducts via nucleotide excision repair (NER) is required for protection against sunlight-associated malignant melanoma. Nonetheless, the extent to which reduced NER capacity might contribute to individual melanoma susceptibility in the general population remains unclear. Here we show that among a panel of 14 human melanoma strains, 11 exhibit significant inhibition of DNA photoproduct removal during S phase relative to G0/G1 or G2/M. Evidence is presented that this cell cycle-specific NER defect correlates with enhanced apoptosis and reduced clonogenic survival following UV irradiation. In addition, melanoma strains deficient in S phase-specific DNA photoproduct removal manifest significantly lower levels of phosphorylated histone H2AX at 1 h post-UV, suggesting diminished activation of ataxia telangiectasia and Rad 3-related (ATR) kinase, i.e., a primary orchestrator of the cellular response to UV-induced DNA replication stress. Consistently, in the case of DNA photoproduct excision-proficient melanoma cells, siRNA-mediated depletion of ATR (but not of its immediate downstream effector kinase Chk1) engenders deficient NER specifically during S. On the other hand simultaneous siRNA-mediated depletion of ataxia telangiectasia mutated kinase (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exerts no significant effect on either phosphorylation of H2AX at 1 h post-UV or the efficiency of DNA photoproduct removal. Our data suggest that defective NER exclusively during S phase, possibly associated with decreased ATR signaling, may constitute an heretofore unrecognized determinant in melanoma pathogenesis.
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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) | 0.003 | 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".