G4 nucleic acid structures act as extra-chromosomal inhibitors in ISG cancer gene regulation.

DNA typically forms a right-handed double helix under physiological conditions but can also form higher-order structures such as a G-quadruplex (G4), formed by guanine-rich nucleic acid sequences. About 10,000 of these exist genome-wide in human chromatin, affecting genetic events including replication, transcription, and translation. They occur particularly in highly transcribed genetic loci, including the promoters and 5′-untranslated regions of cancer-associated genes.

G4 ligands also induce DNA damage response in telomeres, where specialised loop structures protect the ends of linear chromosomes from being recognised as the DNA strand breaks. As telomeres gradually shorten with each cell division, eventually excessive shortening disrupts the loop structure, protection fails, and the DNA damage response kicks in to prompt apoptosis. This process is a fundamental mechanism for tumour suppression.

Separately, upregulation of innate immune/interferon stimulated genes (ISGs) is implicated in cancer progression. Telomeric repeat-containing RNA (TERRA), a long non-coding RNA transcribed from telomeres, and G4-forming oligonucleotides that mimic these have been shown to suppress ISG induction in 3D-culture of cancer cells. The mechanism for this however remains unclear.

Here, Matsumoto et al use liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis equipped with IonOpticks Aurora Series columns to show that splicing factor 3B subunit 2 (SF3B2) is required for ISG induction. They identify SF3B2 as a G4-binding protein, and that its binding to G4-forming oligonucleotides is associated with loss of ISG induction.

These observations reveal a novel function of G4 nucleic acid structures – as an extra-chromosomal, inhibitory, trans-element for gene regulation, to disrupt the ability of SF3B2 to induce ISGs in cancer.

Further, although the authors specifically used TERRA-mimicking oligonucleotides in their experiments, they postulate that other endogenous G4-forming nucleic acids may be involved in specific gene regulation in similar fashion.

Read the full paper
G-quadruplex-forming nucleic acids interact with splicing factor 3B subunit 2 and suppress innate immune gene expression.
Genes Cells. 2021;26:65–82 (8 December 2020). doi: https://doi.org/10.1111/gtc.12824
Matsumoto K, Okamoto K, Okabe S, Fujii R, Ueda K, Ohashi K & Seimiya H

Commentary by Muhammad Zenaidee, PhD

About the author
Muhammad holds a PhD in Chemistry from The University of New South Wales and has a strong background in the development of tools to enhance top-down and bottom-up proteomics. As an Application Scientist at IonOpticks, he utilises his knowledge and training to develop new proteomics tools and technologies for the proteomics community.