Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response

Oncotarget. 2016 Jan 12;7(2):1912-26. doi: 10.18632/oncotarget.6422.


Forkhead box F1 (Foxf1) transcription factor is an important regulator of embryonic development but its role in tumor cells remains incompletely understood. While 16 proteins were characterized in Fanconi anemia (FA) core complex, its interactions with cellular transcriptional machinery remain poorly characterized. Here, we identified FoxF1 protein as a novel interacting partner of the FA complex proteins. Using multiple human and mouse tumor cell lines and Foxf1+/- mice we demonstrated that FoxF1 physically binds to and increases stability of FA proteins. FoxF1 co-localizes with FANCD2 in DNA repair foci in cultured cells and tumor tissues obtained from cisplatin-treated mice. In response to DNA damage, FoxF1-deficient tumor cells showed significantly reduced FANCD2 monoubiquitination and FANCM phosphorylation, resulting in impaired formation of DNA repair foci. FoxF1 knockdown caused chromosomal instability, nuclear abnormalities, and increased tumor cell death in response to DNA-damaging agents. Overexpression of FoxF1 in DNA-damaged cells improved stability of FA proteins, decreased chromosomal and nuclear aberrations, restored formation of DNA repair foci and prevented cell death after DNA damage. These findings demonstrate that FoxF1 is a key component of FA complexes and a critical mediator of DNA damage response in tumor cells.

Keywords: DNA repair; Fanconi anemia protein complex; FoxF1 transcription factor; tumor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Chromatin / genetics
  • Chromosome Aberrations*
  • DNA Damage / genetics*
  • DNA Repair / genetics
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Fluorescent Antibody Technique
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Genomic Instability
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhabdomyosarcoma / drug therapy*
  • Rhabdomyosarcoma / enzymology
  • Rhabdomyosarcoma / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Chromatin
  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • Forkhead Transcription Factors
  • Foxf1 protein, mouse
  • RNA, Messenger