Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites

Caixia Hou; Oleg V. Tsodikov

doi:10.1093/nar/gkaf205

Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites

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Abstract

Ewing sarcoma, a pediatric cancer of bone and soft tissue, is driven in most cases by an abnormal oncogenic fusion of the N-terminal region of EWS with the C-terminal region of FLI1 (EWS-FLI1). The FLI1 region contains a conserved DNA-binding domain (DBD) essential for the oncogenesis. Binding of EWS-FLI1 to microsatellites composed of contiguous GGAA sites, shown previously to be critical for the oncogenic program of this fusion, is not well understood. In this study, we demonstrate that the FLI1 DBD binds cooperatively to contiguous GGAA sites, thereby forming a nucleoprotein filament. A series of crystal structures of two, three, and four FLI1 DBD proteins in complexes with DNA oligomers containing two, three, and four contiguous GGAA sites, respectively, reveal the structure of this filament and the basis for its cooperative formation. We expect this mechanistic insight to be an important milestone in our understanding of the oncogenic function of EWS-FLI1 and exploiting it as a drug target.

Original language	English
Article number	gkaf205
Journal	Nucleic Acids Research
Volume	53
Issue number	6
DOIs	https://doi.org/10.1093/nar/gkaf205
State	Published - Apr 11 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.

Funding

This work was funded by NIH grant R01CA243529. The synchrotron beamline access was supported by the Center for Structural Biology at the University of Kentucky. Funding to pay the Open Access publication charges for this article was provided by the Markey Cancer Center. This work was funded by NIH grant R01CA243529. The synchrotron beamline access was supported by the Center for Structural Biology at the University of Kentucky.\u00A0Funding to pay the\u00A0Open Access publication charges for this article was provided by the Markey Cancer Center.

Funders	Funder number
Center for Structural Biology
University of Kentucky
University of Kentucky Markey Cancer Center
National Institutes of Health (NIH)	R01CA243529
National Institutes of Health (NIH)

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/nar/gkaf205

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title = "Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites",

abstract = "Ewing sarcoma, a pediatric cancer of bone and soft tissue, is driven in most cases by an abnormal oncogenic fusion of the N-terminal region of EWS with the C-terminal region of FLI1 (EWS-FLI1). The FLI1 region contains a conserved DNA-binding domain (DBD) essential for the oncogenesis. Binding of EWS-FLI1 to microsatellites composed of contiguous GGAA sites, shown previously to be critical for the oncogenic program of this fusion, is not well understood. In this study, we demonstrate that the FLI1 DBD binds cooperatively to contiguous GGAA sites, thereby forming a nucleoprotein filament. A series of crystal structures of two, three, and four FLI1 DBD proteins in complexes with DNA oligomers containing two, three, and four contiguous GGAA sites, respectively, reveal the structure of this filament and the basis for its cooperative formation. We expect this mechanistic insight to be an important milestone in our understanding of the oncogenic function of EWS-FLI1 and exploiting it as a drug target.",

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AU - Tsodikov, Oleg V.

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N2 - Ewing sarcoma, a pediatric cancer of bone and soft tissue, is driven in most cases by an abnormal oncogenic fusion of the N-terminal region of EWS with the C-terminal region of FLI1 (EWS-FLI1). The FLI1 region contains a conserved DNA-binding domain (DBD) essential for the oncogenesis. Binding of EWS-FLI1 to microsatellites composed of contiguous GGAA sites, shown previously to be critical for the oncogenic program of this fusion, is not well understood. In this study, we demonstrate that the FLI1 DBD binds cooperatively to contiguous GGAA sites, thereby forming a nucleoprotein filament. A series of crystal structures of two, three, and four FLI1 DBD proteins in complexes with DNA oligomers containing two, three, and four contiguous GGAA sites, respectively, reveal the structure of this filament and the basis for its cooperative formation. We expect this mechanistic insight to be an important milestone in our understanding of the oncogenic function of EWS-FLI1 and exploiting it as a drug target.

AB - Ewing sarcoma, a pediatric cancer of bone and soft tissue, is driven in most cases by an abnormal oncogenic fusion of the N-terminal region of EWS with the C-terminal region of FLI1 (EWS-FLI1). The FLI1 region contains a conserved DNA-binding domain (DBD) essential for the oncogenesis. Binding of EWS-FLI1 to microsatellites composed of contiguous GGAA sites, shown previously to be critical for the oncogenic program of this fusion, is not well understood. In this study, we demonstrate that the FLI1 DBD binds cooperatively to contiguous GGAA sites, thereby forming a nucleoprotein filament. A series of crystal structures of two, three, and four FLI1 DBD proteins in complexes with DNA oligomers containing two, three, and four contiguous GGAA sites, respectively, reveal the structure of this filament and the basis for its cooperative formation. We expect this mechanistic insight to be an important milestone in our understanding of the oncogenic function of EWS-FLI1 and exploiting it as a drug target.

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Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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