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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Detalles Bibliográficos
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
Descripción
Sumario: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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