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Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex
Open accessPreprint — published as 10.1016/j.celrep.2023.113639
Abstract
Summary: The nuclear cap-binding complex (CBC) co-ordinates co-transcriptional maturation, transport, or degradation of nascent Pol II transcripts. CBC with its partner ARS2 form mutually exclusive complexes with diverse ‘effectors’ that promote either productive or destructive outcomes. Combining Alphafold predictions with structural and biochemical validation, we show how effectors NCBP3, NELF-E, ARS2, PHAX and ZC3H18 form competing binary complexes with CBC and how PHAX, NCBP3, ZC3H18 and other effectors compete for binding to ARS2. In ternary CBCA complexes with either PHAX, NCBP3 or ZC3H18, ARS2 is responsible for the initial effector recruitment but inhibits their direct binding to the CBC. We show that in vivo ZC3H18 binding to both CBC and ARS2 is required for nuclear RNA degradation. We propose that recruitment of PHAX to CBC-ARS2 can lead, with appropriate cues, to competitive displacement of ARS2 and ZC3H18 from the CBC, thus promoting a productive rather than a degradative RNA fate.
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Metadata
- Authors
- Dubiez, E., Pellegrini, E., Brask, M. F., Garland, W., Foucher, A.-E., Huard, K., Jensen, T. H., Cusack, S., & Kadlec, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- European Molecular Biology Laboratory (FR)
- Aarhus University (DK)
- Corresponding author
- Cusack, Stephen
- Kadlec, Jan
- ORCID
- Venue
- Cell Reports
- Publisher
- openRxiv
- Published
- 2023-07-25
- Volume
- 43
- Issue
- 1
- Pages
- 113639-113639
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4390585450
- Cited by
- 20
- References
- 1
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 4
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (UAR 3518 CNRS-CEA-UGA-EMBL, ANR-17-EURE-0003, ANR-17-EURE-, ANR-21-CE11-0021, ANR-17, ANR-10, ANR-10-INBS-0005)
- European Synchrotron Radiation Facility
- Novo Nordisk
- Centre National de la Recherche Scientifique (UAR 3518 CNRS-CEA-UGA-EMBL)
- Novo Nordisk Fonden (31199, NNF18OC0033380)
- French Infrastructure for Integrated Structural Biology (ANR-17-EURE-0003, ANR-10-INBS-0005, ANR-10-INBS-000502)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- nuclear cap-binding complex, ARS2, RNA polymerase II transcripts, RNA processing, competitive binding, ternary protein complex, RNA export, protein structure prediction
- MeSH terms
- Binding, Competitive, RNA, RNA Polymerase II, RNA, Nuclear, Nuclear Cap-Binding Protein Complex
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