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Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Abstract

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2−/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2+/− ) can support the development of double-mutant (Aldh2−/−Fancd2−/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2−/−Fancd2−/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.

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Figure 1: Chicken Fanconi anaemia pathway knockout B cells are hypersensitive to acetaldehyde.
Figure 2: A single maternal allele of Aldh2 is essential for the development of Aldh2 −/− Fancd2 −/− mice.
Figure 3: Maternal ethanol exposure aborts the development of Aldh2 −/− Fancd2 −/− embryos.
Figure 4: Ethanol-induced bone marrow failure in Aldh2 −/− Fancd2 −/− mice.
Figure 5: Acute leukaemia in Aldh2 −/− Fancd2 −/− mice.

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Acknowledgements

We thank M. Grompe for Fancd2 knockout mice, J. Sale and S. Takeda for DT40 strains, N. Sugimura and F. Gergely for comments on the manuscript. We are grateful to T. Langford, R. Berks, V. Smith, J. Wiles, C. Shepherd, M. Kidd, M. Brown, A. Mead, R. Pannell, J. Garaycoechea and A. Shortland for their assistance with animal experiments and husbandry. We thank N. Grant and P. Banks from the Visual Aids department for photographic images and W. Zhao of the Human Research Tissue Bank (NIHR Cambridge Biomedical Research Centre) for processing histology. F.L. and I.V.R. are funded by the Children’s Leukaemia Trust and Fanconi Anaemia Research Fund, respectively. K.J.P. acknowledges M. Neuberger, N. McIntyre and C. Desai for support.

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K.J.P., F.L. and G.P.C. designed the experiments. F.L. and G.P.C. performed the majority of the experimental work, I.V.R. contributed to DT40 clonogenic assays and FACS analysis of tumours. M.J.A. carried out histological analysis. K.J.P. wrote the manuscript assisted by F.L. and G.P.C.

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Correspondence to Ketan J. Patel.

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Langevin, F., Crossan, G., Rosado, I. et al. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475, 53–58 (2011). https://doi.org/10.1038/nature10192

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