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Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde

¹ Department of Environmental Sciences and Engineering, and ² Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ³ College of Arts and Sciences, University of Virginia, Charlottesville, Virginia; ⁴ Research Reactor Institute, Kyoto University, Kumatori, Japan; ⁵ Department of Radiation Genetics Graduate School of Medicine, Kyoto, Japan; ⁶ GSF-National Research Center for Environment and Health, Institute for Molecular Radiobiology, Neuherberg-Munich, Germany; ⁷ Beatson Institute for Cancer Research, Glasgow, United Kingdom; ⁸ Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge, United Kingdom; ⁹ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois; and ¹⁰ Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Requests for reprints: Jun Nakamura, Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: 919-966-6140; Fax: 919-966-6123; E-mail: ynakamur{at}email.unc.edu.

Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 µmol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in Fanconi anemia patients. [Cancer Res 2007;67(23):11117–22]

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