HMCES corrupts replication fork stability during base excision repair in homologous recombination deficient cells
Bibliographic record
Abstract
Abstract Apurinic/apyrimidinic (AP) sites and single-strand breaks (SSB) arising from base excision repair (BER) during misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination-deficient (HRD) cells. At templated AP-sites, HMCES DNA-protein crosslinks (DPC) regulate replication fork speed while avoiding APE1-mediated cytotoxic double-strand breaks (DSB). Whereas the role of HMCES at template DNA strand is well studied, its consequences on nascent DNA are less understood. Here, we provide evidence that HMCES play detrimental roles during removal of 5- hydroxymethyl-2’-deoxycytidine (5hmdC)-derived 5-hydroxymethyl-2’-deoxyuridine (5hmdU) by BER at replication forks. HRD cells display heightened HMCES chromatin levels, which increase upon 5hmdC exposure, suggesting that HMCES binds both spontaneous and 5hmdC-induced AP-sites. HMCES depletion largely suppresses 5hmdC- mediated Fancd2 -/- replication fork defects, chromosomal aberrations and cell lethality, suggesting that HMCES is responsible for the replication fork impairment and lethality observed in HRD cells. Therefore, HMCES-DPCs are a novel source of BER-initiated PRIMPOL-mediated ssDNA gaps, implying endogenous DPCs as a source of DNA damage in HRD tumours. Teaser Covalent binding of HMCES to nascent DNA blocks replication progression and kills homologous recombination deficient cancer cells
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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 | 0.000 |
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 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".