Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

Etienne Dubiez; Erika Pellegrini; Maja Finderup Brask; William Garland; Anne Emmanuelle Foucher; Karine Huard; Torben Heick Jensen; Stephen Cusack; Jan Kadlec

doi:10.1016/j.celrep.2023.113639

Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

Etienne Dubiez, Erika Pellegrini, Maja Finderup Brask, William Garland, Anne Emmanuelle Foucher, Karine Huard, Torben Heick Jensen, Stephen Cusack^*, Jan Kadlec^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics - RNA Biology and Innovation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The nuclear cap-binding complex (CBC) coordinates co-transcriptional maturation, transport, or degradation of nascent RNA polymerase II (Pol II) transcripts. CBC with its partner ARS2 forms 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 CBC-ARS2 complexes with 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.

Original language	English
Article number	113639
Journal	Cell Reports
Volume	43
Issue	1
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2023.113639
Publication status	Published - Jan 2024

Keywords

CP: Molecular biology
cryo-EM
protein complexes
RNA biogenesis
RNA degradation

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10.1016/j.celrep.2023.113639

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title = "Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex",

abstract = "The nuclear cap-binding complex (CBC) coordinates co-transcriptional maturation, transport, or degradation of nascent RNA polymerase II (Pol II) transcripts. CBC with its partner ARS2 forms 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 CBC-ARS2 complexes with 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.",

keywords = "CP: Molecular biology, cryo-EM, protein complexes, RNA biogenesis, RNA degradation",

author = "Etienne Dubiez and Erika Pellegrini and {Finderup Brask}, Maja and William Garland and Foucher, {Anne Emmanuelle} and Karine Huard and {Heick Jensen}, Torben and Stephen Cusack and Jan Kadlec",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

month = jan,

doi = "10.1016/j.celrep.2023.113639",

language = "English",

volume = "43",

journal = "Cell Reports",

issn = "2211-1247",

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Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex. / Dubiez, Etienne; Pellegrini, Erika; Finderup Brask, Maja et al.
In: Cell Reports, Vol. 43, No. 1, 113639, 01.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

AU - Dubiez, Etienne

AU - Pellegrini, Erika

AU - Finderup Brask, Maja

AU - Garland, William

AU - Foucher, Anne Emmanuelle

AU - Huard, Karine

AU - Heick Jensen, Torben

AU - Cusack, Stephen

AU - Kadlec, Jan

PY - 2024/1

Y1 - 2024/1

N2 - The nuclear cap-binding complex (CBC) coordinates co-transcriptional maturation, transport, or degradation of nascent RNA polymerase II (Pol II) transcripts. CBC with its partner ARS2 forms 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 CBC-ARS2 complexes with 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.

AB - The nuclear cap-binding complex (CBC) coordinates co-transcriptional maturation, transport, or degradation of nascent RNA polymerase II (Pol II) transcripts. CBC with its partner ARS2 forms 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 CBC-ARS2 complexes with 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.

KW - CP: Molecular biology

KW - cryo-EM

KW - protein complexes

KW - RNA biogenesis

KW - RNA degradation

U2 - 10.1016/j.celrep.2023.113639

DO - 10.1016/j.celrep.2023.113639

M3 - Journal article

C2 - 38175753

AN - SCOPUS:85181836891

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 113639

ER -

Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

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Keywords

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