Elucidating the molecular interactions that determine DDX3X-rich stress granule biogenesis

• Grant number: 25/20129-5
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2026
• End date: January 31, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Ivan Rosa e Silva
• Grantee: Ivan Rosa e Silva
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Ângela Saito ; Juliana Ferreira de Oliveira ; Luis Felipe Santos Mendes

Abstract

Stress granules are dynamic structures formed by the phase separation process that plays crucial roles in the cellular response to environmental stress. The molecular mechanisms regulating the biogenesis of these granules are still poorly characterized. One of the proteins involved in this process is DDX3X, an RNA helicase highly associated with RNA metabolism regulation during neurodevelopment. Loss-of-function mutations in the DDX3X gene have been identified in patients with neurodevelopmental disorders. By integrating methods from cell biology, biochemistry, biophysics, and structural molecular biology, this project aims to investigate the molecular mechanisms regulating the biogenesis of stress granules, focusing on identifying the order of interactions between proteins recruited to DDX3X-rich stress granules. State-of-the-art techniques such as cryo-electron tomography will also be employed, allowing the characterization of the ultrastructure of wild-type DDX3X-rich condensates and their mutant forms that have been related to aberrant stress granule formation. It is expected to obtain a detailed understanding of the molecular mechanisms involved in the cellular functions of DDX3X, also contributing to the understanding of the pathophysiology of diseases associated with mutations in the DDX3X gene. (AU)