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

Abstract

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 Mmol/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

Genetic Analysis of Repair and Damage Tolerance Mechanisms for DNA-Protein Cross-Links in Escherichia coli

“…Recently, the DNA damage response to FA was assessed using chicken DT40 cells with targeted mutations in various DNA repair genes (59). The DT40 cells deficient in HR and TLS were hypersensitive to FA, and those deficient in NER and BER were moderately to slightly sensitive.…”

Molecular pathogenesis and clinical management of Fanconi anemia

“…The defective DNA repair capacity of FA stem cells may underlie their hypersensitivity to endogenous DNA damage, such as damage from ROS (15,99) or from serum formaldehyde (100,101). Such hypersensitivity may lead to decreased hematopoietic cellularity (stem cell loss in early development), similar to phenotypes observed in ATM-deficient or ligase IV-deficient (LIG4-deficient) mice (102,103).…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…Using a mutant cell panel derived from the chicken DT40 cell line, it was shown that cells lacking Fancd2 or Brca2 are particularly sensitive to formaldehyde at concentrations similar to those in normal human serum (Ridpath et al 2007). Patel and coworkers indicated in a series of papers that aldehyde detoxifying enzymes ALDH2 (which mainly catalyzes acetaldehyde) and ADH5 (which mainly catalyzes formaldehyde) play critical roles in FA model mice in the suppression of bone marrow failure and leukemogenesis (Langevin et al 2011, Garaycoechea et al 2012, Oberbeck et al 2014, Pontel et al 2015.…”