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Structural basis of Nuclear Factor 1-X DNA recognition provides prototypic insight into the NFI family

Nuclear Factor I (NFI) proteins are involved in adenovirus DNA replication and regulate gene transcription, stem cell proliferation, and differentiation. They play key roles in development, cancer, and congenital disorders. Within the NFI family, NFI-X is critical for neural stem cell biology, hemat...

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Main Authors: Tiberi, Michele (Author) , Lapi, Michela (Author) , Gourlay, Louise Jane (Author) , Chaves-Sanjuan, Antonio (Author) , Polentarutti, Maurizio (Author) , Demitri, Nicola (Author) , Cavinato, Miriam (Author) , Bonnet, Diane Marie Valérie (Author) , Taglietti, Valentina (Author) , Righetti, Anna (Author) , Sala, Rachele (Author) , Cauteruccio, Silvia (Author) , Kumawat, Amit (Author) , Russo, Rosaria (Author) , Barbiroli, Alberto Giuseppe (Author) , Gnesutta, Nerina (Author) , Camilloni, Carlo (Author) , Bolognesi, Martino (Author) , Messina, Graziella (Author) , Nardini, Marco (Author)
Format: Article (Journal)
Language:English
Published: 19 November 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-14
ISSN:2041-1723
DOI:10.1038/s41467-025-65186-0
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-65186-0
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-65186-0
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Author Notes:Michele Tiberi, Michela Lapi, Louise Jane Gourlay, Antonio Chaves-Sanjuan, Maurizio Polentarutti, Nicola Demitri, Miriam Cavinato, Diane Marie Valérie Bonnet, Valentina Taglietti, Anna Righetti, Rachele Sala, Silvia Cauteruccio, Amit Kumawat, Rosaria Russo, Alberto Giuseppe Barbiroli, Nerina Gnesutta, Carlo Camilloni, Martino Bolognesi, Graziella Messina, and Marco Nardini
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Summary:Nuclear Factor I (NFI) proteins are involved in adenovirus DNA replication and regulate gene transcription, stem cell proliferation, and differentiation. They play key roles in development, cancer, and congenital disorders. Within the NFI family, NFI-X is critical for neural stem cell biology, hematopoiesis, muscle development, muscular dystrophies, and oncogenesis. Here, we present the structural characterization of the NFI transcription factor NFI-X, both alone and bound to its consensus palindromic DNA site. Our analyses reveal a MH1-like fold within NFI-X DNA-binding domain (DBD) and identify crucial structural determinants for activity, such as a Zn²⁺ binding site, dimeric assembly, and DNA-binding specificity. Given the ~85% sequence identity within the NFI DBDs, our structural data are prototypic for the entire family, a NFI Rosetta Stone that allows decoding a wealth of biochemical and functional data and provides a precise target for drug design in a wider disease context.
Item Description:Gesehen am 09.03.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-65186-0

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