Lys‐110 is essential for targeting PCNA to replication and repair foci, and the K110A mutant activates apoptosis
Bibliographic record
Abstract
BACKGROUND INFORMATION: PCNA (proliferating cell nuclear antigen) is required for a wide range of cellular functions, including DNA replication and damage repair. To be functional, PCNA must associate with the replication and repair foci. In addition, PCNA also mediates targeting of certain replication and repair proteins to these foci. However, the mechanism is not yet known by which PCNA is imported into the nucleus, and then localized to the replication and repair foci. RESULTS: We have found that an NLS (nuclear localization sequence) is present within the amino acid 101-120 segment of PCNA. An NLS-deleted PCNA was localized in the cytoplasm and showed 5-fold lower affinity for importin-beta than wild-type, suggesting that PCNA may be imported into the nucleus by importin-beta via its NLS. We previously reported that the functional unit of PCNA is a double trimer (as opposed to single homotrimer), and Lys-110 is essential for the formation of the double trimer complex [Naryzhny, Zhao and Lee (2005) J. Biol. Chem. 280, 13888-13894]. The present study shows that the substitution of Lys-110 within the NLS to an alanine residue did not affect its nuclear localization. However, the double-trimer-defective PCNA(K110A) was not localized at replication or repair foci. In contrast, the double-trimer-intact PCNA(K117A) mutant was targeted normally to replication and repair foci. Interestingly, in cells transfected with PCNA(K110A), but not PCNA(K117A), caspase-3-mediated chromosome fragmentation was activated. CONCLUSIONS: The present study suggests that the regulation of PCNA is intimately connected with that of DNA replication, repair and cell death signals, and raises the possibility that defects in the formation of the PCNA double-trimer complex can cause apoptosis.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | medium |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | high |
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) | 0.002 | 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, unvalidatedLabeled directly by 2 models reading the full record.
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".