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| Title | Structural basis of RNA-guided transcription by a dCas12f-σ-RNAP complex. |
|---|---|
| Journal, issue, pages | Nature, Year 2026 |
| Publish date | Mar 4, 2026 |
 Authors | Renjian Xiao / Florian T Hoffmann / Dan Xie / Tanner Wiegand / Adriana I Palmieri / Samuel H Sternberg / Leifu Chang /  |
| PubMed Abstract | In both natural and engineered biological systems, RNA-guided proteins have emerged as critical transcriptional regulators by modulating RNA polymerase (RNAP) and its associated factors. In bacteria, ...In both natural and engineered biological systems, RNA-guided proteins have emerged as critical transcriptional regulators by modulating RNA polymerase (RNAP) and its associated factors. In bacteria, diverse clades of repurposed TnpB and CRISPR-associated proteins repress gene expression by blocking transcription initiation or elongation, enabling non-canonical modes of regulatory control and adaptive immunity. A distinct class of nuclease-dead Cas12f homologues (dCas12f) instead activates gene expression through its association with unique extracytoplasmic function sigma factors (σ), although the molecular basis has remained elusive. Here we reveal a new mode of RNA-guided transcription initiation by determining the cryo-electron microscopy structures of the dCas12f-σ system from Flagellimonas taeanensis. We captured multiple conformational and compositional states, including the DNA-bound dCas12f-σ-RNAP holoenzyme complex, revealing how RNA-guided DNA binding leads to σ-RNAP recruitment and nascent mRNA synthesis at a precisely defined distance downstream of the R-loop. Rather than following the classical paradigm of σ-dependent promoter recognition, these studies show that recognition of the -35 element is largely supplanted by CRISPR-Cas targeting, whereas the melted -10 element is stabilized through unusual stacking interactions rather than insertion into the typical recognition pocket. Collectively, this work provides high-resolution insights into an unexpected mechanism of RNA-guided transcription, expanding our understanding of bacterial gene regulation and opening new avenues for programmable transcriptional control. |
 External links | Nature / PubMed:41781609 |
| Methods | EM (single particle) |
| Resolution | 2.88 - 3.42 Å |
| Structure data | EMDB-49165, PDB-9n9c: EMDB-49173, PDB-9n9m: EMDB-49174, PDB-9n9o: EMDB-49175, PDB-9n9p: EMDB-49176, PDB-9n9q: |
| Chemicals |  ChemComp-MG:  ChemComp-ZN: |
| Source |
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 Keywords | RNA BINDING PROTEIN/RNA / dCas12f / binary complex / RNA BINDING PROTEIN / RNA BINDING PROTEIN-RNA complex / RNA BINDING PROTEIN/DNA/RNA / partial R-Loop / RNA BINDING PROTEIN-DNA-RNA complex / Full R-Loop / Fta RNAP / RNA polymerase |
flagellimonas taeanensis (bacteria)