title: Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen.
abstract: 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.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Pontel
authors.affiliation: 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.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Rosado
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Burgos-Barragan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Garaycoechea
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2, 2QQ, UK.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chandrasekaran
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Verena
authors.initials: V
authors.lastname: Broecker
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Gerry P
authors.initials: GP
authors.lastname: Crossan
authors.affiliation: 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.
authors.forename: Ketan J
authors.initials: KJ
authors.lastname: Patel
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005557:Formaldehyde / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009153:Mutagens / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D009153:Mutagens; D005557:Formaldehyde; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase