Structural basis of the Integrator complex assembly and association with transcription factors
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Abstract
Integrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs. This is achieved via two enzymatic activities, RNA endonuclease and protein phosphatase, acting on the promoter-proximally paused RNA polymerase Ⅱ (RNAPⅡ). Yet, it remains unclear how Integrator assembly and recruitment are regulated and what the functions of many of its core subunits are. Here, we report the structures of two human Integrator sub-complexes: INTS10/13/14/15 and INTS5/8/10/15, and an integrative model of the fully assembled Integrator bound to the RNAPⅡ paused elongating complex (PEC). An in silico protein-protein interaction screen of over 1,500 human transcription factors (TFs) identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. We propose a model wherein INTS13 acts as a platform for the recruitment of TFs that could modulate the stability of the Integrator’s association at specific loci and regulate transcription attenuation of the target genes.
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- Authors
- Razew, M., Fraudeau, A., Pfleiderer, M. M., Linares, R., & Galej, W. P.
- Affiliations
- European Molecular Biology Laboratory (FR)
- Corresponding author
- Galej, Wojciech P.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2024-07
- Volume
- 84
- Issue
- 13
- Pages
- 2542-2552.e5
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4399212759
- Cited by
- 35
- References
- 8
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 12
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- French Infrastructure for Integrated Structural Biology (ANR-10-INBS-0005-02, ANR-17-EURE-0003)
- European Commission Marie Sklodowska-Curie Actions (847543)
- European Molecular Biology Laboratory (UAR 3518 CNRS-CEA-UGA-EMBL)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- Integrator complex, premature transcription termination, RNA endonuclease, protein phosphatase, RNA polymerase II, promoter-proximal pausing, elongation complex, transcription factor recruitment, protein-protein interaction, transcriptional attenuation, protein complex structure
- MeSH terms
- Binding Sites, Endoribonucleases, Humans, Models, Molecular, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, Transcription Factors, Cryoelectron Microscopy, HEK293 Cells
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