Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation
Open accessPublished version of a preprint
Abstract
Abnormally fast transcription elongation can lead to detrimental consequences such as transcription–replication collisions, altered alternative splicing patterns and genome instability. Therefore, elongating RNA polymerase II (Pol II) requires mechanisms to slow its progression, yet the molecular basis of transcription braking remains unclear. RECQL5 is a DNA helicase that functions as a general elongation factor by slowing down Pol II. Here we report cryo-electron microscopy structures of human RECQL5 bound to multiple transcription elongation complexes. Combined with biochemical analysis, we identify an α-helix of RECQL5 responsible for binding Pol II and slowdown of transcription elongation. We further reveal that the transcription-coupled DNA repair (TCR) complex allows Pol II to overcome RECQL5-induced transcription braking through concerted actions of its translocase activity and competition with RECQL5 for engaging Pol II. Additionally, RECQL5 inhibits TCR-mediated Pol II ubiquitination to prevent activation of the DNA repair pathway. Our results suggest a model in which RECQL5 and the TCR complex coordinately regulate transcription elongation rates to ensure transcription efficiency while maintaining genome stability.
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- Authors
- Zhang, L., Gordiyenko, Y., Morgan, T., Franco, C., Tufegdžić Vidaković, A., & Zhang, S.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Zhang, Suyang
- Venue
- Nature Structural & Molecular Biology
- Published
- 2025-07-07
- Volume
- 32
- Issue
- 9
- Pages
- 1731-1740
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC12440807
- OpenAlex
- W4412093902
- Cited by
- 12
- References
- 9
- Citations by year
- 2026: 8 · 2025: 4
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Apollo (University of Cambridge) (acceptedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- RECQL5, RNA polymerase II, transcription elongation, transcription elongation complex, DNA helicase, transcription-coupled repair, genome stability, alternative splicing, cryo-EM structure
- MeSH terms
- DNA Repair, Humans, Models, Molecular, Protein Binding, RNA Polymerase II, Transcription, Genetic, Cryoelectron Microscopy, RecQ Helicases, Ubiquitination, Transcription Elongation, Genetic
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