Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons
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 G4dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.
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BibTeX
@article{escarcega2026sexlinked,
title = {{Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons}},
author = {Rocio Diaz Escarcega and Vijay Kumar M. J and Ashlee Arizmendez and Chunfeng Tan and Akihiko Urayama and Sean P Marrelli and Rodrigo Morales and Jeffrey S Wefel and Chunchao Zhang and Louise D Mccullough and Nayun Kim and David Monchaud and Sung Yun Jung and Andrey S Tsvetkov},
journal = {Cell Death and Disease},
year = {2026},
month = jun,
doi = {10.1038/s41419-026-08971-z},
url = {https://hal.science/hal-05801648v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons
AU - Rocio Diaz Escarcega
AU - Vijay Kumar M. J
AU - Ashlee Arizmendez
AU - Chunfeng Tan
AU - Akihiko Urayama
AU - Sean P Marrelli
AU - Rodrigo Morales
AU - Jeffrey S Wefel
AU - Chunchao Zhang
AU - Louise D Mccullough
AU - Nayun Kim
AU - David Monchaud
AU - Sung Yun Jung
AU - Andrey S Tsvetkov
PY - 2026
DA - 2026/06/18
JO - Cell Death and Disease
DO - 10.1038/s41419-026-08971-z
UR - https://hal.science/hal-05801648v1
AB - 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 G4dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.
SN - 2041-4889
ER -