G-quadruplex-forming nucleic acids interact with splicing factor 3B subunit 2 and suppress innate immune gene expression

© 2020 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd..

G-quadruplex (G4), a non-canonical higher-order structure formed by guanine-rich nucleic acid sequences, affects various genetic events in cis, including replication, transcription and translation. Whereas up-regulation of innate immune/interferon-stimulated genes (ISGs) is implicated in cancer progression, G4-forming oligonucleotides that mimic telomeric repeat-containing RNA suppress ISG induction in three-dimensional (3D) culture of cancer cells. However, it is unclear how G4 suppresses ISG expression in trans. In this study, we found that G4 binding to splicing factor 3B subunit 2 (SF3B2) down-regulated STAT1 phosphorylation and ISG expression in 3D-cultured cancer cells. Liquid chromatography-tandem mass spectrometry analysis identified SF3B2 as a G4-binding protein. Either G4-forming oligonucleotides or SF3B2 knockdown suppressed ISG induction, whereas Phen-DC3, a G4-stabilizing compound, reversed the inhibitory effect of G4-forming oligonucleotides on ISG induction. Phen-DC3 inhibited SF3B2 binding to G4 in vitro. SF3B2-mediated ISG induction appeared to occur independently of RNA splicing because SF3B2 knockdown did not affect pre-mRNA splicing under the experimental conditions, and pharmacological inhibition of splicing by pladienolide B did not repress ISG induction. These observations suggest that G4 disrupts the ability of SF3B2 to induce ISGs in cancer. We propose a new mode for gene regulation, which employs G4 as an inhibitory trans-element.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:26

Enthalten in:

Genes to cells : devoted to molecular & cellular mechanisms - 26(2021), 2 vom: 19. Feb., Seite 65-82

Sprache:

Englisch

Beteiligte Personen:

Matsumoto, Kyoko [VerfasserIn]
Okamoto, Keiji [VerfasserIn]
Okabe, Sachiko [VerfasserIn]
Fujii, Risa [VerfasserIn]
Ueda, Koji [VerfasserIn]
Ohashi, Kenichi [VerfasserIn]
Seimiya, Hiroyuki [VerfasserIn]

Links:

Volltext

Themen:

60267-61-0
Cancer
Cytokines
Fused-Ring Compounds
G-quadruplex
ISG15 protein, human
Innate immune gene
Interferon-stimulated gene
Journal Article
Ligands
Nucleic Acids
Oligonucleotides
PhenDC3
RNA Splicing Factors
SF3B2
SF3B2 protein, human
STAT1 Transcription Factor
Splicing factor
Telomere
Ubiquitins

Anmerkungen:

Date Completed 15.07.2021

Date Revised 15.07.2021

published: Print-Electronic

GENBANK: GSE157725

Citation Status MEDLINE

doi:

10.1111/gtc.12824

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM318562413