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A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal do...

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Autores principales: Gagliani, Ellen K., Gutzwiller, Lisa M., Kuang, Yi, Odaka, Yoshinobu, Hoffmeister, Phillipp, Hauff, Stefanie, Turkiewicz, Aleksandra, Harding-Theobald, Emily, Dolph, Patrick J., Borggrefe, Tilman, Oswald, Franz, Gebelein, Brian, Kovall, Rhett A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398005/
https://www.ncbi.nlm.nih.gov/pubmed/35951645
http://dx.doi.org/10.1371/journal.pgen.1010335
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author Gagliani, Ellen K.
Gutzwiller, Lisa M.
Kuang, Yi
Odaka, Yoshinobu
Hoffmeister, Phillipp
Hauff, Stefanie
Turkiewicz, Aleksandra
Harding-Theobald, Emily
Dolph, Patrick J.
Borggrefe, Tilman
Oswald, Franz
Gebelein, Brian
Kovall, Rhett A.
author_facet Gagliani, Ellen K.
Gutzwiller, Lisa M.
Kuang, Yi
Odaka, Yoshinobu
Hoffmeister, Phillipp
Hauff, Stefanie
Turkiewicz, Aleksandra
Harding-Theobald, Emily
Dolph, Patrick J.
Borggrefe, Tilman
Oswald, Franz
Gebelein, Brian
Kovall, Rhett A.
author_sort Gagliani, Ellen K.
collection PubMed
description Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.
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spelling pubmed-93980052022-08-24 A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects Gagliani, Ellen K. Gutzwiller, Lisa M. Kuang, Yi Odaka, Yoshinobu Hoffmeister, Phillipp Hauff, Stefanie Turkiewicz, Aleksandra Harding-Theobald, Emily Dolph, Patrick J. Borggrefe, Tilman Oswald, Franz Gebelein, Brian Kovall, Rhett A. PLoS Genet Research Article Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation. Public Library of Science 2022-08-11 /pmc/articles/PMC9398005/ /pubmed/35951645 http://dx.doi.org/10.1371/journal.pgen.1010335 Text en © 2022 Gagliani et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gagliani, Ellen K.
Gutzwiller, Lisa M.
Kuang, Yi
Odaka, Yoshinobu
Hoffmeister, Phillipp
Hauff, Stefanie
Turkiewicz, Aleksandra
Harding-Theobald, Emily
Dolph, Patrick J.
Borggrefe, Tilman
Oswald, Franz
Gebelein, Brian
Kovall, Rhett A.
A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title_full A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title_fullStr A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title_full_unstemmed A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title_short A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
title_sort drosophila su(h) model of adams-oliver syndrome reveals cofactor titration as a mechanism underlying developmental defects
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398005/
https://www.ncbi.nlm.nih.gov/pubmed/35951645
http://dx.doi.org/10.1371/journal.pgen.1010335
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