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Structural insights into promoter-proximal pausing of RNA polymerase II at +1 nucleosome

Masahiro Naganuma, Tomoya Kujirai, Haruhiko Ehara, Tamami Uejima, Tomoko Ito, Mie Goto, Mari Aoki, Masami Henmi, Sayako Miyamoto-Kohno, Mikako Shirouzu, Hitoshi Kurumizaka, Shun-Ichi Sekine

Abstract
The metazoan transcription elongation complex (EC) of RNA polymerase II (RNAPII) generally stalls between the transcription start site and the first (+1) nucleosome. This promoter-proximal pausing involves negative elongation factor (NELF), 5,6-dichloro-1-β-d-ribobenzimidazole sensitivity-inducing factor (DSIF), and transcription elongation factor IIS (TFIIS) and is critical for subsequent productive transcription elongation. However, the detailed pausing mechanism and the involvement of the +1 nucleosome remain enigmatic. Here, we report cryo-electron microscopy structures of ECs stalled on nucleosomal DNA. In the absence of TFIIS, the EC is backtracked/arrested due to conflicts between NELF and the nucleosome. We identified two alternative binding modes of NELF, one of which reveals a critical contact with the downstream DNA through the conserved NELF-E basic helix. Upon binding with TFIIS, the EC progressed to the nucleosome to establish a paused EC with a partially unwrapped nucleosome. This paused EC strongly restricts EC progression further downstream. These structures illuminate the mechanism of RNAPII pausing/stalling at the +1 nucleosome.

Science Advances, doi: 10.1126/sciadv.adu0577. (2025)
https://www.science.org/doi/10.1126/sciadv.adu0577