Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde
- 1 December 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (23), 11117-11122
- https://doi.org/10.1158/0008-5472.can-07-3028
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 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]Keywords
Other Versions
This publication has 18 references indexed in Scilit:
- Interplay between DNA polymerases β and λ in repair of oxidation DNA damage in chicken DT40 cellsDNA Repair, 2007
- Poly(ADP-ribose): novel functions for an old moleculeNature Reviews Molecular Cell Biology, 2006
- Targeted Disruption of FANCC and FANCG in Human Cancer Provides a Preclinical Model for Specific Therapeutic OptionsGastroenterology, 2006
- Rad18 Regulates DNA Polymerase κ and Is Required for Recovery from S-Phase Checkpoint-Mediated ArrestMolecular and Cellular Biology, 2006
- The Fanconi Anemia/BRCA pathway: new faces in the crowdGenes & Development, 2005
- Multiple Repair Pathways Mediate Tolerance to Chemotherapeutic Cross-linking Agents in Vertebrate CellsCancer Research, 2005
- Meeting Report: Summary of IARC Monographs on Formaldehyde, 2-Butoxyethanol, and 1- tert -Butoxy-2-PropanolEnvironmental Health Perspectives, 2005
- Loss of DNA–protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome functionCarcinogenesis: Integrative Cancer Research, 2000
- Comparison of Inhaled Formaldehyde Dosimetry Predictions with DNA–Protein Cross-Link Measurements in the Rat Nasal PassagesToxicology and Applied Pharmacology, 1997
- Efficiency of DNA-histone crosslinking induced by saturated and unsaturated aldehydes in vitroMutation Research Letters, 1992