Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.
Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Houston, US · Author affiliation
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.Location evidence
Santiago, CL · Author affiliation
Centro Integrativo de Biologia y Quimica Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile.Location evidence
Baltimore, US · Author affiliation
Department of Otorhinolaryngology, Head and Neck Surgery, The University of Maryland School of Medicine, Baltimore, MD, USA.Location evidence
US · Author affiliation · country only
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.Location evidence
Dijon, FR · Author affiliation
Institut De Chimie Moléculaire de l'Université de Bourgogne (ICMUB), Université Bourgogne Europe (UBE), Dijon, France.Location evidence
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Original abstract
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 female and male 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 response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.