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Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure

Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and F...

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Autores principales: Vierra, David A., Garzon, Jada L., Rego, Meghan A., Adroved, Morganne M., Mauro, Maurizio, Howlett, Niall G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652718/
https://www.ncbi.nlm.nih.gov/pubmed/29100324
http://dx.doi.org/10.18632/oncotarget.19470
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author Vierra, David A.
Garzon, Jada L.
Rego, Meghan A.
Adroved, Morganne M.
Mauro, Maurizio
Howlett, Niall G.
author_facet Vierra, David A.
Garzon, Jada L.
Rego, Meghan A.
Adroved, Morganne M.
Mauro, Maurizio
Howlett, Niall G.
author_sort Vierra, David A.
collection PubMed
description Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown. In this study, we have examined the influence of chromatin state on the activation of the FA pathway. We describe potent activation of FANCD2 and FANCI monoubiquitination and nuclear foci formation following treatment of cells with the histone methyltransferase inhibitor BRD4770. BRD4770-induced activation of the pathway does not occur via the direct induction of DNA damage or via the inhibition of the G9a histone methyltransferase, a mechanism previously proposed for this molecule. Instead, we show that BRD4770-inducible FANCD2 and FANCI monoubiquitination and nuclear foci formation may be a consequence of inhibition of the PRC2/EZH2 chromatin-modifying complex. In addition, we show that inhibition of the class I and II histone deacetylases leads to attenuated FANCD2 and FANCI monoubiquitination and nuclear foci formation. Our studies establish that chromatin state is a major determinant of the activation of the FA pathway and suggest an important role for the PRC2/EZH2 complex in the regulation of this critical tumor suppressor pathway.
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spelling pubmed-56527182017-11-02 Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure Vierra, David A. Garzon, Jada L. Rego, Meghan A. Adroved, Morganne M. Mauro, Maurizio Howlett, Niall G. Oncotarget Research Paper Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown. In this study, we have examined the influence of chromatin state on the activation of the FA pathway. We describe potent activation of FANCD2 and FANCI monoubiquitination and nuclear foci formation following treatment of cells with the histone methyltransferase inhibitor BRD4770. BRD4770-induced activation of the pathway does not occur via the direct induction of DNA damage or via the inhibition of the G9a histone methyltransferase, a mechanism previously proposed for this molecule. Instead, we show that BRD4770-inducible FANCD2 and FANCI monoubiquitination and nuclear foci formation may be a consequence of inhibition of the PRC2/EZH2 chromatin-modifying complex. In addition, we show that inhibition of the class I and II histone deacetylases leads to attenuated FANCD2 and FANCI monoubiquitination and nuclear foci formation. Our studies establish that chromatin state is a major determinant of the activation of the FA pathway and suggest an important role for the PRC2/EZH2 complex in the regulation of this critical tumor suppressor pathway. Impact Journals LLC 2017-07-22 /pmc/articles/PMC5652718/ /pubmed/29100324 http://dx.doi.org/10.18632/oncotarget.19470 Text en Copyright: © 2017 Vierra et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Vierra, David A.
Garzon, Jada L.
Rego, Meghan A.
Adroved, Morganne M.
Mauro, Maurizio
Howlett, Niall G.
Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title_full Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title_fullStr Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title_full_unstemmed Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title_short Modulation of the Fanconi anemia pathway via chemically induced changes in chromatin structure
title_sort modulation of the fanconi anemia pathway via chemically induced changes in chromatin structure
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652718/
https://www.ncbi.nlm.nih.gov/pubmed/29100324
http://dx.doi.org/10.18632/oncotarget.19470
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