A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production-Reference-Cited by-同舟云学术

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

Published:2023-05-19 Issue:20 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Wit Niek¹²^ORCID,Gogola Ewa²³^ORCID,West James A.¹,Vornbäumen Tristan¹,Seear Rachel V.¹,Bailey Peter S. J.¹^ORCID,Burgos-Barragan Guillermo²⁴,Wang Meng²⁵⁶,Krawczyk Patrycja²^ORCID,Huberts Daphne H. E. W.²⁷,Gergely Fanni⁷⁸^ORCID,Matheson Nicholas J.¹⁹^ORCID,Kaser Arthur¹¹⁰^ORCID,Nathan James A.¹^ORCID,Patel Ketan J.²³^ORCID

Affiliation:

1. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, UK.

2. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.

3. MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.

4. Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

5. Department of Haematology, University of Cambridge, Cambridge, UK.

6. Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.

7. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.

8. Department of Biochemistry, University of Oxford, Oxford, UK.

9. NHS Blood and Transplant, Cambridge, UK.

10. Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adg2235

Reference47 articles.

1. Formaldehyde Carcinogenicity Research

2. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans

3. Formaldehyde Dehydrogenase from Human Liver

4. Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen

5. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response

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