Abstract

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.

Highlights

  • Fanconi anemia (FA) is characterized by bone marrow failure and predisposition to malignancies including leukemia and young-onset squamous cell carcinomas (SCCs) of the head and neck and of the esophagus [1]

  • Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

  • These results suggest that acetaldehyde causes DNA damage in the esophagus, the nature of acetaldehyde-induced DNA damage was not investigated in these studies

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Summary

Introduction

Fanconi anemia (FA) is characterized by bone marrow failure and predisposition to malignancies including leukemia and young-onset squamous cell carcinomas (SCCs) of the head and neck and of the esophagus [1]. When the DNA replication machinery encounters an ICL, 13 FA proteins (FANCA, B, C, E, F, G, L, M, and T; FA-associated proteins FAAP10, FAAP16, FAAP24, FAAP100) form the FA core complex at the replication fork [4,5] This core complex acts as the E3 ubiquitin ligase for FANCI-FANCD2 complex, which, together with the ATR cell cycle checkpoint kinase, plays a critical role in coordinating downstream DNA repair processes. These repair processes include nucleotide excision repair (NER), translesion synthesis (TLS), and homologous recombination (HR), all of which are required to complete ICL repair in order to resume DNA replication and preserve genomic integrity [4,5]

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