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

Arun Pradhan,Vladimir V Kalinichenko,Tanya V Kalin,Yufang Zhang,Vladimir Ustiyan

doi:10.18632/oncotarget.6422

Arun Pradhan, Vladimir V Kalinichenko + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.6422

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Journal: Oncotarget	Publication Date: Nov 28, 2015
Citations: 23	License type: cc-by

Affiliation: Cincinnati Children's Hospital Medical Center

Abstract

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.

Highlights

Cancer cells possess diverse phenotypic features which distinguish them from their nonmalignant counterparts
Among multiple transcription factors screened in this assay, endogenous Forkhead Box F1 (FoxF1) protein was found to bind the HF-FANCM along with its known interacting partners, such as FANCA, FANCI, FAAP100, FAAP20, MHF1 and MHF2 (Figure 1A)
Previous studies with FoxF1-deficient mice have shown that FoxF1 is an important transcriptional regulator of embryonic development [49,50,51], its role in DNA repair of tumor cells remains uncharacterized

Summary

Introduction

Cancer cells possess diverse phenotypic features which distinguish them from their nonmalignant counterparts. In order to attain a state of chromosomal instability, cancer cells inhibit DNA damage response by accumulating inactivating mutations in genes critical for DNA repair pathways, including genes encoding subunits of Fanconi anemia complex [4]. The hallmark cellular feature of cells derived from FA patients includes chromosomal instability and hypersensitivity to crosslinking agents, such as mitomycin C (MMC), Cisplatin and diepoxybutane (DEB) [9,10]. This rare cancer-prone disease has generated wide-spread attention because the proteins involved in FA have led to the elucidation of a repair pathway for interstrand DNA crosslinks (ICL)

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