Targeting G3BP1: Discovery of a Novel Modulator of Stress Granule Dynamics
Abstract
Stress granule (SG) biology has emerged as a therapeutic target in several disease pathologies. Stress response plays an important role in maintaining cellular homeostasis under adverse conditions, yet this same pathway can be exploited by cancer cells and viral pathogens to promote cancer cell survival, viral replication, and disease progression. The work presented in this dissertation investigates the molecular mechanisms underlying SG biology with a focus on protein-protein interactions (PPIs). This dissertation explores strategies to target SG processes as potential therapeutics in cancer, viral infection, and environmentally induced malignancy.SGs are dynamic ribonucleoprotein condensates that form under environmental and genotoxic stresses. G3BP1 is a core component of SGs and its interactions with other proteins regulate the nucleation and assembly of SGs. Using a time-resolved fluorescence resonance energy transfer (TR-FRET) screening approach targeting the G3BP1 NTF2-like (NTF2L) domain, small-molecule ligands were identified that disrupt G3BP1 interactions and suppress SG formation. The first application of the G3BP1-targeting small molecules is to test whether they enhance cisplatin-induced cytotoxicity of triple-negative breast cancer (TNBC) cells. My results show that these ligands suppressed SGs, sensitized TNBC cells to cisplatin, and increased DNA damage signaling and apoptosis, supporting that disruption of SG assembly can sensitize cancer cells to…
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