Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen

Lucas B Pontel,Ivan V Rosado,Guillermo Burgos-Barragan,Juan I Garaycoechea,Rui Yu,Mark J Arends,Gayathri Chandrasekaran,Verena Broecker,Wei Wei,Limin Liu,James A Swenberg,Gerry P Crossan,Ketan J Patel

doi:10.1016/j.molcel.2015.08.020

Abstract

SummaryEndogenous 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.

Highlights

alcohol dehydrogenase 5 (ADH5) Prevents Endogenous Formaldehyde from Forming DNA Adducts It is clear that numerous cytoplasmic and nuclear pathways release formaldehyde, which is detectable in human blood at significant levels (Luo et al, 2001)
Dilution analysis reveals that the expression of ADH5 in the bone marrow is between 32- and 64-fold lower than in the kidney (Figure 1B)
Endogenous formaldehyde can be produced in proximity to chromosomes, potentially enabling it to react with DNA

Summary

Graphical Abstract

Formaldehyde is a ubiquitous, highly reactive molecule that is a byproduct of metabolism; Pontel et al show how mammals protect themselves against this metabolic toxin and what happens if this protection is removed. Highlights d ADH5 removes endogenous formaldehyde to prevent DNA adducts d ADH5 and FANCD2 protect HSCs, hepatocytes, and nephrons from endogenous DNA damage d Bone marrow transplantation provides protection against formaldehyde nephrotoxicity d Endogenous formaldehyde is a potent carcinogen.

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