HMCES corrupts replication fork stability during base excision repair in homologous recombination–deficient cells
Bibliographic record
Abstract
Apurinic/apyrimidinic (AP) sites and single-strand breaks arising from base excision repair (BER) during the misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination-deficient (HRD) cells. At templated AP sites, cross-links between the DNA and 5-hydroxymethylcytosine binding, embryonic stem cell-specific (HMCES) regulate replication fork speed, avoiding cytotoxic double-strand breaks. While the role of HMCES at the template DNA strand is well studied, its effects on nascent DNA are not. We provide evidence that HMCES-DNA-protein cross-links (DPCs) are detrimental to the BER-mediated removal of 5-hydroxymethyl-2'-deoxycytidine (5hmdC)-derived 5-hydroxymethyl-2'-deoxyuridine from replication forks. HRD cells have heightened HMCES-DPCs, which increase further upon 5hmdC exposure, suggesting that HMCES binds both spontaneous and 5hmdC-induced AP sites. HMCES depletion substantially suppresses 5hmdC-mediated replication fork defects, chromosomal aberrations, and cell death in HRD cells. This reveals that HMCES-DPCs are a source of BER-initiated single-stranded DNA gaps, which indicates that endogenous DPCs contribute to genomic instability in HRD tumors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".