Mol Cell. 2015 Oct 1;60(1):177-88. doi: 10.1016/j.molcel.2015.08.020. Epub 2015 Sep 24.

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

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MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Instituto de Biomedicina de Sevilla (IBiS) Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
University of Edinburgh Division of Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2, 2QQ, UK.
Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK. Electronic address: kjp@mrc-lmb.cam.ac.uk.


Endogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5(-/-) mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5(-/-)Fancd2(-/-) mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.

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