RNA helicase DDX3 regulates RAD51 localization and DNA damage repair in Ewing sarcoma

Randolph, Matthew E.; Afifi, Marwa; Gorthi, Aparna; Weil, Rachel; Wilky, Breelyn A.; Weinreb, Joshua; Ciero, Paul; Hoeve, Natalie ter; van Diest, Paul J.; Raman, Venu; Bishop, Alexander J.R.; Loeb, David M.

doi:10.1016/j.isci.2024.108925

Cited by 1 publication

(1 citation statement)

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“…These mutations may disrupt the phase separation properties of DDX3X, leading to altered stress granule dynamics or dysregulated RNA metabolism, which could contribute to cancer development. Indeed, previous studies have implicated DDX3X in various aspects of cancer biology, including cell cycle regulation, apoptosis, and metastasis [35][36][37]. Our findings suggest that mutations in RG/RGG motifs may represent a novel mechanism by which DDX3X contributes to cancer pathogenesis.…”

Section: Discussionmentioning

confidence: 51%

Cell-Free Analysis Reveals the Role of RG/RGG Motifs in DDX3X Phase Separation and Their Potential Link to Cancer Pathogenesis

Chen,

Li,

Zhao

et al. 2024

Preprint

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The DEAD-box RNA helicase DDX3X is a multifunctional protein involved in RNA metabolism and stress responses. In this study, we investigated the role of RG/RGG motifs in the dynamic process of liquid-liquid phase separation (LLPS) of DDX3X using cell-free assays and explored their potential link to cancer development through bioinformatic analysis. Our results demonstrate that the number, location, and composition of RG/RGG motifs significantly influence the ability of DDX3X to undergo phase separation and form self-aggregates. Mutational analysis revealed that the spacing between RG/RGG motifs and the number of glycine residues within each motif are critical factors in determining the extent of phase separation. Bioinformatic analysis of cancer genomic datasets uncovered a significant enrichment of DDX3X mutations in RG/RGG motifs across multiple cancer types, particularly in the N-terminal region of the protein. Furthermore, we found that DDX3X is co-expressed with the stress granule protein G3BP1 in several cancer types and can undergo co-phase separation with G3BP1 in a cell-free system, suggesting a potential functional interaction between these proteins in phase-separated structures. DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently exert important cellular functions under stress situation. Collectively, our findings provide novel insights into the role of RG/RGG motifs in modulating DDX3X phase separation and their potential contribution to cancer pathogenesis.

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Section: Discussionmentioning

confidence: 51%