Clastogenesis by nucleotide lesions requires the completion of two cell cycles
Bibliographic record
Abstract
Abstract Damaged DNA nucleotides can trigger genome rearrangements through clastogenesis, a process driven by erroneous repair of double-strand breaks (DSBs) and associated with cancer development. While DSBs are known to arise from endonuclease activity at stalled replication forks, the clastogenic potential of such DSBs has remained uncertain. Here, we identify a previously unrecognized mechanism of clastogenesis using wild-type, nucleotide excision repair (NER)-deficient and translesion synthesis (TLS)-deficient cells, combined with advanced cytogenetic analyses. We demonstrate that, single-stranded DNA (ssDNA) tracts harboring unrepaired lesions rather than DSBs at collapsed replication forks can persist through mitosis. Only during the subsequent S phase, these tracts are converted into a new class of, highly clastogenic, DSBs. Consistent with a role of this mechanism in carcinogenesis, prostate cancers exhibiting extensive genomic rearrangements frequently harbor somatic defects in NER or in error-free homologous recombination-mediated DSB repair. These findings provide critical mechanistic insight and highlight potential implications for routine clastogenicity testing. Graphical abstract Nucleotide lesions (light blue triangle) can trigger double-strand breaks (DSBs) through endonucleolytic cleavage at stalled or reversed replication forks. Traditionally, these DSBs were assumed to drive genome rearrangements, a process termed clastogenesis. Here we describe a distinct, delayed, mechanism of clastogenesis. Thus, unreplicated nucleotide lesions within single-stranded (ss) DNA regions persist through mitosis into the next cell cycle. During the subsequent S phase, these ssDNA tracts collapse into DSBs, presumably via replication runoff. These delayed DSBs then promote extensive genomic reshuffling. Supporting this model, prostate cancers with high levels of genomic rearrangements are frequently associated with somatic defects in nucleotide excision repair (NER)—a pathway that normally prevents lesion-induced clastogenesis.
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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) | 0.004 | 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".