Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions

Kinga Winczura, Manfred Schmid, Claudia Iasillo, Kelly R Molloy, Lea Mørch Harder, Jens S Andersen, John LaCava, Torben Heick Jensen

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Abstract

Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins. Further examination of ZC3H18 function, by genome-wide analyses, demonstrated its impact on transcription of a subset of protein-coding genes. This activity requires the CBC-interacting domain of the protein, with some genes being also dependent on the NEXT- and/or histone-interacting domains. Our data shed light on the domain requirements of a protein positioned centrally in nuclear RNA metabolism, and they suggest that post-translational modification may modulate its function.

Original languageEnglish
JournalCell Reports
Volume22
Issue number1
Pages (from-to)44-58
ISSN2211-1247
DOIs
Publication statusPublished - 2. Jan 2018

Fingerprint

RNA
Exosomes
Nuclear RNA
Proteins
Genes
Histones
Metabolism
RNA Cap-Binding Proteins
Mutagenesis
Phosphorylation
Transcription
Protein Isoforms
Screening

Keywords

  • CBC
  • NEXT
  • RNA decay
  • RNA exosome
  • ZC3H18
  • histones
  • transcription

Cite this

Winczura, Kinga ; Schmid, Manfred ; Iasillo, Claudia ; Molloy, Kelly R ; Harder, Lea Mørch ; Andersen, Jens S ; LaCava, John ; Jensen, Torben Heick. / Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions. In: Cell Reports. 2018 ; Vol. 22, No. 1. pp. 44-58.
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abstract = "Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins. Further examination of ZC3H18 function, by genome-wide analyses, demonstrated its impact on transcription of a subset of protein-coding genes. This activity requires the CBC-interacting domain of the protein, with some genes being also dependent on the NEXT- and/or histone-interacting domains. Our data shed light on the domain requirements of a protein positioned centrally in nuclear RNA metabolism, and they suggest that post-translational modification may modulate its function.",
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Winczura, K, Schmid, M, Iasillo, C, Molloy, KR, Harder, LM, Andersen, JS, LaCava, J & Jensen, TH 2018, 'Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions', Cell Reports, vol. 22, no. 1, pp. 44-58. https://doi.org/10.1016/j.celrep.2017.12.037

Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions. / Winczura, Kinga; Schmid, Manfred; Iasillo, Claudia; Molloy, Kelly R; Harder, Lea Mørch; Andersen, Jens S; LaCava, John; Jensen, Torben Heick.

In: Cell Reports, Vol. 22, No. 1, 02.01.2018, p. 44-58.

Research output: Contribution to journalJournal articleResearchpeer-review

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T1 - Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions

AU - Winczura, Kinga

AU - Schmid, Manfred

AU - Iasillo, Claudia

AU - Molloy, Kelly R

AU - Harder, Lea Mørch

AU - Andersen, Jens S

AU - LaCava, John

AU - Jensen, Torben Heick

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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N2 - Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins. Further examination of ZC3H18 function, by genome-wide analyses, demonstrated its impact on transcription of a subset of protein-coding genes. This activity requires the CBC-interacting domain of the protein, with some genes being also dependent on the NEXT- and/or histone-interacting domains. Our data shed light on the domain requirements of a protein positioned centrally in nuclear RNA metabolism, and they suggest that post-translational modification may modulate its function.

AB - Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins. Further examination of ZC3H18 function, by genome-wide analyses, demonstrated its impact on transcription of a subset of protein-coding genes. This activity requires the CBC-interacting domain of the protein, with some genes being also dependent on the NEXT- and/or histone-interacting domains. Our data shed light on the domain requirements of a protein positioned centrally in nuclear RNA metabolism, and they suggest that post-translational modification may modulate its function.

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KW - NEXT

KW - RNA decay

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KW - ZC3H18

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DO - 10.1016/j.celrep.2017.12.037

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JF - Cell Reports

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