Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia-Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network

Jessy Abraham, Silvia Balbo, David Crabb, Phillip J. Brooks

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa-ADH1B cells with ethanol (20mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N 2-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network.

Original languageEnglish (US)
Pages (from-to)2113-2120
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Fanconi Anemia
Acetaldehyde
Metabolism
DNA Damage
Ethanol
Cells
Alcohols
Breast Neoplasms
Phosphorylation
DNA
HeLa Cells
DNA Adducts
Alcohol Dehydrogenase
Chemical activation
Human Body
Drinking

Keywords

  • Acetaldehyde
  • Alcohol Dehydrogenase
  • Breast Cancer
  • DNA Adducts
  • Hepatocellular Carcinoma
  • N2-Ethyldeoxyguanosine

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia-Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network. / Abraham, Jessy; Balbo, Silvia; Crabb, David; Brooks, Phillip J.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 12, 12.2011, p. 2113-2120.

Research output: Contribution to journalArticle

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abstract = "Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa-ADH1B cells with ethanol (20mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N 2-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network.",
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