Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage
Bibliographic record
Abstract
In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms and of checkpoints that delay cell cycle progression to allow more time for DNA repair. Inhibiting both responses with drugs might cause cancer cells to undergo cell division in the presence of lethal amounts of unrepaired DNA. However, we show that interfering with DNA repair via inhibition of DNA-dependent protein kinase (DNA-PK) reduces the ability of checkpoint inhibitors to abrogate G2 arrest and their radiosensitizing activity. Cells exposed to the DNA-PK inhibitor AMA37, DNA-PK-deficient cells, and nonhomologous end joining-deficient cells all enter prolonged G2 arrest after exposure to ionizing radiation doses as low as 2 Gy. The checkpoint kinase Chk2 becomes rapidly and transiently overactivated, whereas Chk1 shows sustained overactivation that parallels the prolonged accumulation of cells in G2. Therefore, in irradiated cells, DNA repair inhibition elicits abnormally strong checkpoint signaling that causes essentially irreversible G2 arrest and strongly reduces the ability of checkpoint kinase inhibitors to overcome G2 arrest and radiosensitize cells. Variable levels of proteins controlling DNA repair have been documented in cancer cells. Therefore, these results have relevance to the development of DNA-PK inhibitors and G2 checkpoint inhibitors as experimental therapeutic approaches to enhance the selective killing of tumor cells by radiotherapy or DNA-damaging chemotherapeutic agents.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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".