A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production
Niek Wit, Ewa Gogola, James A. West, Tristan Vornbäumen, Rachel Seear, Peter S. J. Bailey, Guillermo Burgos-Barragan, Meng Wang, Patrycja A. Krawczyk, Daphne H. E. W. Huberts, Fanni Gergely, Nicholas J. Matheson, Arthur Kaser, James A. Nathan, Ketan J. Patel
Abstract
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.