Abstract
The forkhead box (Fox) transcription factors (TFs) are widespread from yeast to humans. Their mutations and dysregulation have been linked to a broad spectrum of malignant neoplasias. They are known as critical players in DNA repair, metabolism, cell cycle control, differentiation, and aging. Recent studies, especially those from the simple model eukaryotes, revealed unexpected contributions of Fox TFs in chromosome replication and organization. More importantly, besides functioning as a canonical TF in cell signaling cascades and gene expression, Fox TFs can directly participate in DNA replication and determine the global replication timing program in a transcription-independent mechanism. Yeast Fox TFs preferentially recruit the limiting replication factors to a subset of early origins on chromosome arms. Attributed to their dimerization capability and distinct DNA binding modes, Fkh1 and Fkh2 also promote the origin clustering and assemblage of replication elements (replication factories). They can mediate long-range intrachromosomal and interchromosomal interactions and thus regulate the four-dimensional chromosome organization. The novel aspects of Fox TFs reviewed here expand their roles in maintaining genome integrity and coordinating the multiple essential chromosome events. These will inevitably be translated to our knowledge and new treatment strategies of Fox TF-associated human diseases including cancer.
Highlights
They are known as critical players in DNA repair, metabolism, cell cycle control, differentiation, and aging
This study suggests that forkhead box (Fox) transcription factors (TFs), from another aspect, affects DNA replication by regulating the supply of building blocks of nucleic acids [8]
Besides operating as TFs for transcription of the genes involved in DNA synthesis and cell cycle control, Fox family proteins were recently shown to have some direct roles in DNA replication timing
Summary
The DNA-binding specificities of different forkhead proteins were intensively examined (Figure 2). The canonical forkhead target sequence is RYAAAYA, which is referred to as the forkhead primary (FkhP) motif. A similar variant, AHAACA, was identified during in vitro selection and protein-binding microarray experiments for several Fox proteins. It was designated as the forkhead secondary (FkhS). A third motif, (G)ACGC, is called the FHL motif, which is the preferred binding site of FoxN1, N4, and Fhl in vitro and in vivo [4]. JASPAR, an open-access database (http://jaspar.genereg.net) {Fornes, 2020 #174}
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