期刊
GENES TO CELLS
卷 26, 期 2, 页码 65-82出版社
WILEY
DOI: 10.1111/gtc.12824
关键词
cancer; G‐ quadruplex; innate immune gene; interferon‐ stimulated gene; splicing factor; telomere
资金
- Japan Society for the Promotion of Science [18K07252, 20H04789, 20K21555]
- Japan Agency for Medical Research and Development
- Nippon Foundation
- Grants-in-Aid for Scientific Research [20H04789, 20K21555, 18K07252] Funding Source: KAKEN
G-quadruplex (G4) can suppress ISG expression in cancer cells by binding to splicing factor 3B subunit 2 (SF3B2), providing a new mode for gene regulation.
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.
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