DYNLL1 mis-splicing is associated with replicative genome instability in SF3B1 mutant cells
Bibliographic record
Abstract
ABSTRACT Genome instability is a hallmark of cancer that arises through a panoply of mechanisms driven by oncogene and tumour-suppressor gene mutations. Oncogenic mutations in the core splicing factor SF3B1 have been linked to genome instability. Since SF3B1 mutations alter the selection of thousands of 3’ splice sites affecting genes across biological pathways, it is not entirely clear how they might drive genome instability. Here we confirm that while R-loop formation and associated replication stress may account for some of the SF3B1-mutant genome instability, a mechanism involving changes in gene expression also contributes. An SF3B1-H662Q mutant cell line mis-splices the 5’UTR of the DNA repair regulator DYNLL1, leading to higher DYNLL1 protein levels, mis-regulation of DNA repair pathway choice and PARP inhibitor sensitivity. Reduction of DYNLL1 protein in these cells restores genome stability. Together these data highlight how SF3B1 mutations can alter cancer hallmarks through subtle changes to the transcriptome.
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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 | 0.001 |
| 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, 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".