Cryo-EM structure of DDM1-HELLS chimera bound to nucleosome reveals a mechanism of chromatin remodeling and disease regulation
Bibliographic record
Abstract
Abstract Human HELicase, Lymphoid Specific (HELLS), and plant homolog Deficient in DNA Methylation 1 (DDM1), belong to a distinct class of chromatin remodelers that play important roles in DNA repair, transcription, and maintenance of DNA methylation in heterochromatin. HELLS also promotes the growth of hard-to-treat cancers including glioblastoma and hepatocellular carcinoma. Here, we identify an auto-inhibitory HELLS N-terminal coiled-coil, unravelling a long-standing question of HELLS inactivity in vitro . Using cryo-EM, we determine the 3.5 Å structure of an active DDM1-HELLS chimera in complex with a nucleosome. The structure reveals that a HELLS-specific insertion in the ATPase lobe 2 interacts with the nucleosome acidic patch to enhance chromatin remodeling. At the C-terminus, we resolve a unique motif, and disease hot spot, that binds and stabilizes the ATPase motor of the HELLS family of remodelers. Finally, we provide mechanistic insights for how post-translational modifications in the motor domain and midloop could modulate HELLS activity to regulate cancer stem cell state.
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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 | 0.001 | 0.001 |
| 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".