Toward a mechanistic understanding of DNA binding by forkhead transcription factors and its perturbation by pathogenic mutations

Forkhead box (FOX) proteins are an evolutionarily conserved family of transcription factors that play numerous regulatory roles in eukaryotes during developmental and adult life. Dysfunction of FOX proteins has been implicated in a variety of human diseases, including cancer, neurodevelopment disorders and genetic diseases. The FOX family members share a highly conserved DNA-binding domain (DBD), which is essential for DNA recognition, binding and function. Since the first FOX structure was resolved in 1993, >30 FOX structures have been reported to date. It is clear now that the structure and DNA recognition mechanisms vary among FOX members; however, a systematic review on this aspect is lacking. In this manuscript, we present an overview of the mechanisms by which FOX transcription factors bind DNA, including protein structures, DNA binding properties and disease-causing mutations. This review should enable a better understanding of FOX family transcription factors for basic researchers and clinicians.

Automated summary

FOX proteins are an evolutionarily conserved family of transcription factors that play regulatory roles in eukaryotes, with dysfunction implicated in various human diseases. Despite sharing a highly conserved DNA-binding domain, differences exist in the structure and DNA recognition mechanisms among FOX family members, calling for further systematic reviews.