Regulation of 5′ template usage and incorporation of noncognate nucleotides by human telomerase
Bibliographic record
Abstract
Telomerase accurately synthesizes telomeric DNA by reverse transcription of a tightly defined template region in the telomerase RNA (TR). Reverse transcription past the 5' boundary of the template can cause the incorporation of noncognate nucleotides into telomeric DNA, which can result in disruption of normal telomere function. The products synthesized by human telomerase do not contain the nucleotide cytosine, which is encoded by an hTR residue 2 nucleotides (nt) 5' of the template boundary. We examined dCTP incorporation by a series of telomerases reconstituted with N- and C-terminally mutated human telomerase reverse transcriptases (hTERTs). We found that altering sequences in the N-terminal RNA interaction domain 1 (RID1) and C terminus caused dCTP-dependent catalytic phenotypes suggestive of reverse transcription of sequences 5' of the template boundary. A RID1 mutant that exhibited a dCTP-dependent phenotype interacted less efficiently with a human telomerase RNA (hTR) variant in which the 5' template boundary-defining P1b element was disrupted, whereas C-terminal mutations did not alter hTR interactions in a P1b-dependent fashion. Disruption of P1b or template linker sequences between P1b and the 5' template boundary also impaired 5' template usage in RID1 and C-terminal hTERT mutants. These observations identify overlapping roles for hTR sequences and structures 5' of the template in regulating both 5' template boundary definition and 5' template usage, and implicate hTERT N- and C-terminal regions in 5' template usage and suppression of noncognate nucleotide incorporation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".