Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde.
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 micromol/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.
Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
John R
JR
Ridpath
Ayumi
A
Nakamura
Keizo
K
Tano
April M
AM
Luke
Eiichiro
E
Sonoda
Hiroshi
H
Arakawa
Jean-Marie
JM
Buerstedde
David A F
DA
Gillespie
Julian E
JE
Sale
Mitsuyoshi
M
Yamazoe
Douglas K
DK
Bishop
Minoru
M
Takata
Shunichi
S
Takeda
Masami
M
Watanabe
James A
JA
Swenberg
Jun
J
Nakamura
D000079:Acetaldehyde / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004202:Disinfectants / Q000097:blood* / Q000494:pharmacology; D005199:Fanconi Anemia; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D005557:Formaldehyde / Q000097:blood* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006037:Glyoxal / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology; D011995:Recombination, Genetic; D015398:Signal Transduction
D000447:Aldehydes; D019313:BRCA1 Protein; D003432:Cross-Linking Reagents; D004202:Disinfectants; D052236:Fanconi Anemia Complementation Group D2 Protein; D005557:Formaldehyde; D006037:Glyoxal; D011765:Pyruvaldehyde; D000171:Acrolein; C012796:2-butenal; D005978:Glutathione; D000079:Acetaldehyde