Cryo-EM uncovers a sequential mechanism for RNA polymerase I pausing and stalling at abasic DNA lesions

During synthesis of the ribosomal RNA precursor, RNA polymerase I (Pol I) monitors DNA integrity but its response to DNA damage remains poorly studied. Abasic sites are among the most prevalent DNA lesions in eukaryotic cells, and their detection is critical for cell survival. We report cryo-EM structures of Pol I in different stages of stalling at abasic sites, supported by in vitro transcription studies. Slow nucleotide addition opposite abasic sites occurs through base sandwiching between the RNA 3'-end and the Pol I bridge helix. Templating abasic sites can also cause Pol I cleft opening, which enables the A12 subunit to access the active center. Nucleotide addition opposite the lesion induces a translocation intermediate where DNA bases tilt to form hydrogen bonds with the new RNA base. These findings reveal unique mechanisms of Pol I stalling at abasic sites, differing from arrest by bulky lesions or abasic site handling by RNA polymerase II.

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Publication Details

Journal
Nature Communications
Published
2025-06-06
DOI
https://doi.org/10.1038/s41467-025-60536-4
Citations
1
Primary Topic
Advanced Electron Microscopy Techniques and Applications
Type
article
Field-Weighted Citation Impact
2.55

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article

Cryo-EM uncovers a sequential mechanism for RNA polymerase I pausing and stalling at abasic DNA lesions

Peini Hou, Jun Xu, Federico M. Ruiz, Marta Sanz Murillo et al.
1 citations
Nature Communications
Advanced Electron Microscopy Techniques and Applications
2.55
article

Cryo-EM uncovers a sequential mechanism for RNA polymerase I pausing and stalling at abasic DNA lesions

Peini Hou, Jun Xu, Federico M. Ruiz, Marta Sanz Murillo, Adrián Plaza-Pegueroles, Carlos Fernández‐Tornero, David Gil‐Carton, Alicia Santos-Aledo, Dong Wang
article en
1 citations

Abstract

During synthesis of the ribosomal RNA precursor, RNA polymerase I (Pol I) monitors DNA integrity but its response to DNA damage remains poorly studied. Abasic sites are among the most prevalent DNA lesions in eukaryotic cells, and their detection is critical for cell survival. We report cryo-EM structures of Pol I in different stages of stalling at abasic sites, supported by in vitro transcription studies. Slow nucleotide addition opposite abasic sites occurs through base sandwiching between the RNA 3'-end and the Pol I bridge helix. Templating abasic sites can also cause Pol I cleft opening, which enables the A12 subunit to access the active center. Nucleotide addition opposite the lesion induces a translocation intermediate where DNA bases tilt to form hydrogen bonds with the new RNA base. These findings reveal unique mechanisms of Pol I stalling at abasic sites, differing from arrest by bulky lesions or abasic site handling by RNA polymerase II.

Nature CommunicationsVol. 16(1)
Ikerbasque (ES), University of the Basque Country (ES), Instituto Biofisika (ES), Centro de Investigaciones Biológicas Margarita Salas (ES), University of Montana (US)
Diamond Light Source, European Commission, Eusko Jaurlaritza, Euskal Herriko Unibertsitatea, Agencia Estatal de Investigación, National Institute of General Medical Sciences, European Social Fund
Zero hunger
Openalex Percentile: Top 11%
Advanced Electron Microscopy Techniques and Applications
2.55
DOIOpen Access PDFOpenAlex
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