An analysis of the interplay between telomeric factors and DNA repair proteins, in the human ALT pathway and cellular response to genomic double strand breaks
Bibliographic record
Abstract
Telomeres are nucleoprotein structures that cap the ends of linear eukaryotic chromosomes and consist of repetitive telomeric DNA (T2AG 3)n as well as telomere specific proteins, such as TRF1 and TRF2. Telomeres escape detection by the DNA double strand break damage response network (DDRN), however they shorten with each successive cell division and activate the DDRN at a critical length, which causes growth arrest. Cellular immortalization requires the activation of a telomere maintenance pathway. The majority of tumors and immortalized cell lines achieve this by expression of telomerase, which adds de novo telomere repeats to the ends of chromosomes. Telomerase-negative immortalized human cells maintain telomeres by alternative lengthening of telomeres (ALT) pathway(s), which may involve homologous recombination. We find that the DNA repair protein, BLM co-localizes with telomeric foci in ALT human cells but not telomerase positive immortal cell lines or primary cells. BLM interacts in vivo with the telomeric protein TRF2 in ALT cells, as detected by FRET and co-immunoprecipitation. Transient over-expression of green fluorescent protein (GFP)-BLM results in marked, ALT cell-specific increases in telomeric DNA. The association of BLM with telomeres and its effect on telomere DNA synthesis require a functional helicase domain. We also find that inhibition of BLM expression by siRNA causes ALT-specific telomere dysfunction, as evidenced by an increase of chromosome end-to-end fusions. Our results identify BLM as the first protein to affect telomeric DNA synthesis exclusively in human ALT cells and suggest that BLM facilitates recombination-driven amplification of telomeres. In addition to describing a role for a DNA repair protein in telomere maintenance, we provide the first demonstration for the involvement of a human telomere-specific protein (TRF2), in the cellular response to genomic DNA double strand breaks (DSBs). TRF2 migrates to sites of genomic DSBs within 2 seconds post-DNA damage and is independent of other known DNA repair proteins. This migration is not dependent on its affinity for telomeric DNA or its myb DNA binding domain, but requires its basic domain. Over-expression of TRF2 attenuates the ATM dependent DNA damage response, which suggests that TRF2 is involved in the initial stages of sensing/processing genomic DSBs.
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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) | 0.001 | 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".