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

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Wit, Niek 
Gogola, Ewa 
West, James 
Vornbäumen, Tristan 
Seear, Rachel 

Cells produce considerable genotoxic formaldehyde from an unknown source. Here we carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells which 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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Science Advances
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American Association for the Advancement of Science
Wellcome Trust (215477/Z/19/Z)
Lister Institute of Preventive Medicine (unknown)
Addenbrooke's Charitable Trust (ACT) (900188 Minute 03/19 C4)
Wellcome Senior Clinical Research Fellowship 215477/Z/19/Z (J.A.N.) Lister Institute Research Fellowship (J.A.N.); Addenbrooke’s Charitable Trust (J.A.N.) Medical Research Council (MRC) (K.J.P.) Cancer Research UK (CRUK) C42693/A23273 (K.J.P.) Wellcome Trust 106202/Z/14/Z (K.J.P.) Rubicon ZonMw 45219116 (E.G.) Rubicon ZonMW 019.161LW.040 (D.H.E.W.H.) Trinity Hall, Cambridge University (G.B.B) Human Frontier Science Program LT000571/2019-L (G.B.B.) CRUK C60150/A23919 (M.W.) CRUK Clinician Scientist Fellowship C60150/A23919 (M.W.) CRUK C14303/A17197 and A24455 (F.G. and D.H.E.W.H.) Wellcome Trust Early-Career Award 225102/Z/22/Z (E.G.) Wellcome Investigator Award 222497/Z/21/Z (A.K.) MRC Transition Support Fellowship MR/T032413/1 (N.J.M.) NHSBT research grant WPA15-02 (N.J.M.) NIHR Cambridge BRC (N.J.M.) Wellcome Trust Institutional Strategic Support Fund 204845/Z/16/Z ( N.J.M.) Wellcome PhD Training Fellowship for Clinicians 205252/Z/16/Z (P.S.J.B).