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Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents

Changmin Chen; Diane R. Wonsey; Madeleine E. Lemieux; Andrew L. Kung

Title:
Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents
Author(s):
Chen, Changmin
Wonsey, Diane R.
Lemieux, Madeleine E.
Kung, Andrew L.
Date:
Type:
Articles
Department(s):
Pediatrics
Volume:
8
Persistent URL:
Book/Journal Title:
PLoS ONE
Publisher:
Public Library of Science
Abstract:
Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA. In contrast, actinomycin D was found to preferentially disrupt EWS-FLI1 binding by comparison to p53 binding to their respective cognate DNA targets in vitro. In cell-based assays, low concentrations of actinomycin D preferentially blocked EWS-FLI1 binding to chromatin, and disrupted EWS-FLI1-mediated gene expression. Higher concentrations of actinomycin D globally repressed transcription. These results demonstrate that actinomycin D preferentially disrupts EWS-FLI1 binding to DNA at selected concentrations. Although the window between this preferential effect and global suppression is too narrow to exploit in a therapeutic manner, these results suggest that base-preferences may be exploited to find DNA-binding compounds that preferentially disrupt subclasses of transcription factors.
Subject(s):
Gene expression
DNA-binding proteins
Ewing's sarcoma
Molecular biology
Genetics
Oncology
Publisher DOI:
https://doi.org/10.1371/journal.pone.0069714
Item views
38
Metadata:
text | xml
Suggested Citation:
Changmin Chen, Diane R. Wonsey, Madeleine E. Lemieux, Andrew L. Kung, , Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents, Columbia University Academic Commons, .

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