Loss of DHX36/G4R1, a G4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

SUMMARY G-quadruplexes (G4s) are four-stranded alternative secondary structures formed by guanine-rich nucleic acids and prevalent across the human genome. G4s enzymatically resolved using specialized helicases. Previous in vitro studies showed that DEAH-box Helicase 36 (DHX36/G4R1/RHAU), has highest specificity affinity for G4 structures. Here, mapping genome-wide DNA double-strand breaks (DSBs), we demonstrate knockout (KO) of DHX36 helicase increases DSB enrichment at sites presence motif is a significant mediator genome instability regulatory regions. The loss corresponds with upregulation NF-κB transcriptional programs, culminating production secretion proinflammatory cytokines. Loss expression results an increase innate immune signaling stimulator interferon response cGAMP interactor 1 ( STING1 ) activation genes involved pathways. Importantly, higher levels mRNA B-cell acute lymphoblastic leukemia correlate improved overall survival relative to lower , highlighting its critical role preserving integrity cellular level context cancer.

Language: Английский

Enriched G4 forming repeats in the human genome are associated with robust well-coordinated transcription and reduced cancer transcriptome variation

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 107822 - 107822

Published: Sept. 1, 2024

Language: Английский