The Emerging Roles of Fox Family Transcription Factors in Chromosome Replication, Organization, and Genome Stability

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.

Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER

“…These are the Fkh, highly conserved transcription factors in eukaryotes, from yeast to human, with roles in physiological processes and diseases. Human Fkh molecules have been intensively studied due to their crucial function in cellular processes such as cell cycle regulation 66 , 67 , genome replication and stability 68 , aging and oxidative stress 69 , 70 , metabolism 71 , 72 , cancer 73 – 76 , and neurodegeneration 77 . The human Fkh family comprises 18 subfamilies 78 , 79 , with two of them named Forkhead box O (FoxO) and M (FoxM) being the closest functional counterpart of the budding yeast Fkh1 and Fkh2.…”

MiR‐1471 protects the aggravation of non‐small‐cell lung carcinoma by targeting FOXL1

“…21,22 It is reported that FOXL1 is involved in the TGF-p1 signaling by targeting Smad2, BMP-7, and TGF-131. 21,22 FOXL1 is a transcription factor expressed in mesenchymal cells of the gastrointestinal tract. The homology of the Forkhead region with FOXL1 at nucleotide level is as high as 83%, suggesting that FOXL1 may be involved in the regulation of TGFβ/Smads signaling, and thus participates in tumor progression.…”

GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

“…This sequence was very similar to the consensus GLISBS reported previously 32, 46, 47 , indicating that our ChIP-Seq was successful in detecting specific GLIS1 binding sequences. Our GLIS1 ChIP-Seq analysis identified a number of additional motifs, including motifs for bZIP transcription factors (e.g., ATF3, FRA1, BATF, and JUNB, members of the AP-1 complex), forkhead box (FOX) proteins 48 , and TEA domain transcription factors (TEAD) that play a key role in the Hippo pathway 49 . These data suggested co-localization of the GLIS1 binding consensus with motifs for other transcription factors that have been previously implicated in the regulation of TM and glaucoma 45, 50, 51 .…”