HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP- ribose modifications
Bibliographic record
Abstract
ABSTRACT Upon detecting DNA strand breaks, PARP1 and PARP2 produce the posttranslational modification poly(ADP-ribose) to orchestrate the cellular response to DNA damage. Histone PARylation factor 1 (HPF1) binds to PARP1/2 to directly regulate their catalytic output. HPF1 is required for the modification of serine residues with ADP-ribose, whereas glutamate/aspartate residues are modified in the absence of HPF1. PARP1 is an abundant nuclear protein, whereas HPF1 is present in much lower amounts, raising the question of whether HPF1 can pervasively modulate PARP1 activity. Here we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at the sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates and dissociates from multiple PARP1 molecules, initiating ADP-ribose modification of serine residues before modification can initiate on glutamate/aspartate residues. HPF1 accelerates the rate of attaching the first ADP-ribose, such that this initiation event is comparable to the rate of the elongation reaction to form poly(ADP-ribose). This “hit and run” mechanism ensures that HPF1 contributions to the PARP1/2 active site during initiation do not persist and interfere with PAR chain elongation at sites of DNA damage. HPF1 thereby balances initiation and elongation events to regulate PARP1/2 output. Structural analysis of HPF1 in complex with PARP1 provides first insights into the assembly on a DNA strand break, and the HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of the serine-ADP-ribose modification in cells and establish that HPF1 imparts the efficiency of serine-ADP-ribose modification required for an acute response to DNA damage.
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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 | 0.001 |
| 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".