DNA Double Strand Break Repair in Mitosis Is Suppressed by Phosphorylation of XRCC4
Bibliographic record
Abstract
Cells are continuously subjected to DNA damage, the most cytotoxic form of which is the DNA double-strand break (DSB).DSBs arise from endogenous sources, such as collapsed replication forks, or can be caused by exogenous agents that include ionizing radiation, reactive oxygen species, and chemotherapeutic drugs such as topoisomerase II poisons [1].During interphase, DSBs are repaired by one of two main pathways: classical non-homologous end joining (C-NHEJ) or homologous recombination repair (HRR) [2].The fate of DSBs that arise during mitosis, however, has been poorly characterized.In this issue of PLOS Genetics, Shinohara and colleagues demonstrate that DSB induction in mitosis leads to the formation of anaphase bridges, a hallmark of genomic instability, and demonstrate that their formation requires primarily the C-NHEJ pathway [3].C-NHEJ, which is active throughout interphase, is considered a rapid but errorprone pathway that rejoins DSB ends with minimal end processing.The main steps in C-NHEJ are detection of the DSB by the Ku heterodimer, followed by recruitment of end-processing factors and the DNA ligase IV-XRCC4-XLF complex.Regulation of C-NHEJ end processing is controlled by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [4,5].HRR, on the other hand, occurs only in S and G2 and is initiated by the binding of the MRN complex (composed of Mre11, Rad50, and Nbs1), which is followed by MRN-and CtIP-mediated resection to create long 39 overhanging ends required for Rad51-dependent strand invasion.Unlike C-NHEJ, HRR requires an undamaged DNA template for repair, usually the sister chromatid, and results in slower, but more precise, repair [6].In addition to the two main repair pathways, DSBs can also be repaired by an error-prone, alternative end-joining pathway (Alt-NHEJ).Alt-NHEJ requires end-resection and involves CtIP, XRCC1, and DNA ligase III, but not the C-NHEJ factors [7].DSBs initiate an elaborate signaling cascade that involves protein phosphorylation
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".