Prolonged G2 arrest and Chk1 overactivation following DNA damage in the absence of DNA-PK activity
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 46, 2005 4435 Cells can respond to DNA damage by activating DNA repair mechanisms and cell cycle checkpoints. In the absence of p53, the G2/M DNA damage checkpoint represents the final chance for a cell to prevent transmission of damaged DNA to daughter cells. DNA-PK is a crucial component of the non-homologous end joining (NHEJ) DNA double-strand break repair machinery. Although it belongs to the same PI3-like kinase family as ATM and ATR, it is generally believed not to have a G2 checkpoint function because it is not required to initiate G2 arrest after DNA damage. However, we show that human glioma M059J and rodent CHO V3 cells lacking the DNA-PK catalytic subunit enter a prolonged G2 arrest after exposure to ionizing radiation while their DNA-PK-proficient counterparts M059K, M059J/Fus1 and CHO V3 cells transfected with hDNA-PKcs only undergo a transient arrest. G2 accumulation is observed at the clinical-dose of 2 Gy in DNA-PK-deficient cells, while DNA-PK-proficient cells failed to exhibit any arrest at this dose. The prolonged arrest is observed up to 48 hours post-irradiation (IR) in both DNA-PK-deficient cell lines. This arrest is accompanied by a strong overactivation of Chk1, and decreased CDK1 activation. Also, the ATM/ATR inhibitor caffeine, as well as the Chk1/Chk2 inhibitor isogranulatimide (Jiang et al., 2004. Mol. Can. Ther. 3:1221) exhibit decreased activity in DNA-PKcs deficient cells, indicating a strengthened checkpoint response. Prolonged G2 arrest is similarly observed when DNA-PK-proficient cells are exposed to the selective DNA-PK inhibitor AMA37 (Knight et al., 2004. Bioorg. Med. Chem. 12:4749), but not when cells are exposed to 200 nM wortmannin. This arrest is dependent on maintaining DNA-PK inhibition, which must be present at the time irradiation. Irradiation of M059 cells in late-S/G2 caused no prolonged arrest, suggesting the role DNA-PK plays in the maintenance of the G2 checkpoint lies in its NHEJ function, with DNA lesions leading to an extended checkpoint response.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".