Research Papers:

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

Arun Pradhan, Vladimir Ustiyan, Yufang Zhang, Tanya V. Kalin and Vladimir V. Kalinichenko _

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Oncotarget. 2016; 7:1912-1926. https://doi.org/10.18632/oncotarget.6422

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Arun Pradhan1, Vladimir Ustiyan1, Yufang Zhang1, Tanya V. Kalin1, Vladimir V. Kalinichenko1

1Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children’s Research Foundation, Cincinnati, OH 45229, USA

Correspondence to:

Vladimir V. Kalinichenko, e-mail: [email protected]

Arun Pradhan, e-mail: [email protected]

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

Received: July 21, 2015     Accepted: November 15, 2015     Published: November 28, 2015


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.

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