A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production

Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellu...

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Autores principales: Wit, Niek, Gogola, Ewa, West, James A., Vornbäumen, Tristan, Seear, Rachel V., Bailey, Peter S. J., Burgos-Barragan, Guillermo, Wang, Meng, Krawczyk, Patrycja, Huberts, Daphne H. E. W., Gergely, Fanni, Matheson, Nicholas J., Kaser, Arthur, Nathan, James A., Patel, Ketan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Biomedicine and Life Sciences
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10191432/
https://www.ncbi.nlm.nih.gov/pubmed/37196082
http://dx.doi.org/10.1126/sciadv.adg2235
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author Wit, Niek
Gogola, Ewa
West, James A.
Vornbäumen, Tristan
Seear, Rachel V.
Bailey, Peter S. J.
Burgos-Barragan, Guillermo
Wang, Meng
Krawczyk, Patrycja
Huberts, Daphne H. E. W.
Gergely, Fanni
Matheson, Nicholas J.
Kaser, Arthur
Nathan, James A.
Patel, Ketan J.
author_facet Wit, Niek
Gogola, Ewa
West, James A.
Vornbäumen, Tristan
Seear, Rachel V.
Bailey, Peter S. J.
Burgos-Barragan, Guillermo
Wang, Meng
Krawczyk, Patrycja
Huberts, Daphne H. E. W.
Gergely, Fanni
Matheson, Nicholas J.
Kaser, Arthur
Nathan, James A.
Patel, Ketan J.
author_sort Wit, Niek
collection PubMed
description Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.
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spelling pubmed-101914322023-05-18 A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production Wit, Niek Gogola, Ewa West, James A. Vornbäumen, Tristan Seear, Rachel V. Bailey, Peter S. J. Burgos-Barragan, Guillermo Wang, Meng Krawczyk, Patrycja Huberts, Daphne H. E. W. Gergely, Fanni Matheson, Nicholas J. Kaser, Arthur Nathan, James A. Patel, Ketan J. Sci Adv Biomedicine and Life Sciences Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite. American Association for the Advancement of Science 2023-05-17 /pmc/articles/PMC10191432/ /pubmed/37196082 http://dx.doi.org/10.1126/sciadv.adg2235 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Wit, Niek
Gogola, Ewa
West, James A.
Vornbäumen, Tristan
Seear, Rachel V.
Bailey, Peter S. J.
Burgos-Barragan, Guillermo
Wang, Meng
Krawczyk, Patrycja
Huberts, Daphne H. E. W.
Gergely, Fanni
Matheson, Nicholas J.
Kaser, Arthur
Nathan, James A.
Patel, Ketan J.
A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title_full A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title_fullStr A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title_full_unstemmed A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title_short A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
title_sort histone deacetylase 3 and mitochondrial complex i axis regulates toxic formaldehyde production
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10191432/
https://www.ncbi.nlm.nih.gov/pubmed/37196082
http://dx.doi.org/10.1126/sciadv.adg2235
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