Phosphorylation of Claspin by elF2α kinase protects cells from heat stress
Bibliographic record
Abstract
Abstract Various biological stresses can induce replication stress, potentially leading to cancer development. Replication checkpoint protects cells against the threat of DNA damages by suspending cell cycle, allowing DNA repair. Chk1 kinase is activated by various stresses and is required for replication checkpoint. An adaptor protein, Claspin, mediates Chk1 activation, but specific mechanisms involved are still unknown. We demonstrate that heat stress induces hyperphosphorylation of Claspin, resulting in Chk1 activation. Claspin phosphorylation is impaired in cells lacking two eIF2α kinases, GCN2 and HRI, which are parts of the integrated stress response (ISR) pathway. Mass spectrometry identified five heat-inducible phosphorylation sites in the C-terminal region of Claspin, and Claspin lacking these sites failed to activate checkpoint. Our data support a model that the unphosphorylated C-terminal tail of Claspin masks its CKBD (Chk1 Binding Domain)-AP (Acidic Patch) domain, preventing it from interacting with Cdc7. Phosphorylation of the tail causes it to dissociate from CKBD-AP and facilitates Cdc7 interaction, leading to increased Chk1 activation. Our findings demonstrate crosstalk between replication checkpoint and ISR pathways, and suggest potential new strategies for cancer therapy.
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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) | 0.002 | 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, 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".