FANCD2 limits acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes

Mol Oncol. 2021 Nov;15(11):3109-3124. doi: 10.1002/1878-0261.13072. Epub 2021 Aug 8.


Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and one of the major carcinogens in humans. However, the molecular basis of acetaldehyde-induced genomic instability in SCCs of the head and neck and of the esophagus in FA remains elusive. Here, we report the effects of acetaldehyde on replication stress response in esophageal epithelial cells (keratinocytes). Acetaldehyde-exposed esophageal keratinocytes displayed accumulation of DNA damage foci consisting of 53BP1 and BRCA1. At physiologically relevant concentrations, acetaldehyde activated the ATR-Chk1 pathway, leading to S- and G2/M-phase delay with accumulation of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, suggesting that acetaldehyde impedes replication fork progression. Consistently, depletion of the replication fork protection protein Timeless led to elevated DNA damage upon acetaldehyde exposure. Furthermore, FANCD2 depletion exacerbated replication abnormalities, elevated DNA damage, and led to apoptotic cell death, indicating that FANCD2 prevents acetaldehyde-induced genomic instability in esophageal keratinocytes. These observations contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol-related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs.

Keywords: FANCD2; Fanconi anemia; acetaldehyde; alcohol; esophageal squamous cell carcinoma; genomic instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaldehyde / metabolism
  • Acetaldehyde / toxicity
  • DNA Damage
  • DNA Repair / genetics
  • DNA Replication / genetics
  • Esophagus / pathology
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism
  • Fanconi Anemia* / genetics
  • Fanconi Anemia* / metabolism
  • Fanconi Anemia* / pathology
  • Genomic Instability
  • Humans
  • Keratinocytes / metabolism


  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Acetaldehyde