Oxidative stress accelerates repeat sequence instability and base substitutions promoting gastrointestinal driver mutations in MSH2 deficient mice
Bibliographic record
Abstract
Abstract Background Loss of DNA mismatch repair (MMR) increases mutagenesis and tumorigenesis. mutS homolog 2 (MSH2), a central component of the MMR pathway, is essential for correcting base–base mismatches and insertion/deletion loops during DNA replication. To investigate how Msh2 deficiency cooperates with oxidative stress to drive mutagenesis and tumorigenesis, we employed an rpsL reporter gene assay using normal tissues before tumor development following treatment with an oxidizing agent. Results The background mutation frequency in the small intestines of Msh2 -/- mice was over 20-fold higher than that of wild-type mice. In addition to G > A base substitutions, frequent 1-bp deletions in adenine mononucleotide repeats ((A)n) in the rpsL gene were observed. Potassium bromate treatment further increased the mutation frequency, particularly insertion-deletion mutations (indel), in the normal small intestinal epithelium of Msh2 -/- mice before tumor development. Mutation signature analysis from next-generation sequencing data revealed that signatures associated with MMR deficiency (SBS15, SBS44, and ID2) and clock-like processes (SBS1 and SBS5) were consistently detected across all Msh2 -/- tumors, similar to those observed in human MMR-deficient cancers. ID2, which involves 1-base deletions occurring in (A/T) n tracts of six bases or longer, supports the findings of the rpsL assay. Microsatellite instability (MSI) analysis showed that indel mutations at (A)n loci detected using the rpsL assay reflect genome-wide MSI. Msh2 -/- tumors frequently harbored driver mutations, such as frameshift mutations in short tandem repeats within Apc and G > A substitutions in Ctnnb1 , both of which activate the Wnt signaling pathway. Oxidative stress further accelerated these mutational processes. Conclusion Oxidative stress promotes repeat-associated mutagenesis, which manifests as MSI and base substitutions in MMR-deficient intestinal tissues, thereby enhancing the mutator phenotype and increasing the overall mutation burden. This process can be sensitively captured using our rpsL assay, which serves as a functional indicator of MMR deficiency and replication instability in normal tissues before tumor formation. This increases the likelihood of driver mutations in oncogenes and tumor suppressor genes, ultimately accelerating early tumorigenesis. This study demonstrated that MSH2 is essential for maintaining genome stability under oxidative conditions and functions as a key suppressor of oxidative stress–induced tumorigenesis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 0.000 |
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 teacher head, 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".