Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons

作者：Rocio Diaz Escarcega, Vijay Kumar M J, Ashlee Arizmendez, Chunfeng Tan, Akihiko Urayama, Sean P. Marrelli, Rodrigo Morales, Jeffrey S. Wefel, Chunchao Zhang, Louise D. McCullough, Nayun Kim, David Monchaud, Sung Yun Jung, Andrey S. Tsvetkov · 发表于：Cell Death and Disease · 年份：2026 · DOI：10.1038/s41419-026-08971-z · 研究领域：DNA and Nucleic Acid Chemistry、DNA Repair Mechanisms、RNA Research and Splicing

G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage r...