Abstract
It is now more than 20 years since the FRA16D common chromosomal fragile site was characterised and the WWOX gene spanning this site was identified. In this time, much information has been discovered about its contribution to disease; however, the normal biological role of WWOX is not yet clear. Experiments leading to the identification of the WWOX gene are recounted, revealing enigmatic relationships between the fragile site, its gene and the encoded protein. We also highlight research mainly using the genetically tractable model organism Drosophila melanogaster that has shed light on the integral role of WWOX in metabolism. In addition to this role, there are some particularly outstanding questions that remain regarding WWOX, its gene and its chromosomal location. This review, therefore, also aims to highlight two unanswered questions. Firstly, what is the biological relationship between the WWOX gene and the FRA16D common chromosomal fragile site that is located within one of its very large introns? Secondly, what is the actual substrate and product of the WWOX enzyme activity? It is likely that understanding the normal role of WWOX and its relationship to chromosomal fragility are necessary in order to understand how the perturbation of these normal roles results in disease.
Highlights
Chromosomal Fragile Site Genes—The Precedent of FRA3B/FHIT Chromosomal fragile sites are of interest for a number and variety of reasons [1]
The common fragile sites vary in the frequency with which they respond to induction—the FRA3B site on human chromosome 3 being most readily observed, followed by FRA16D on chromosome 16, others [1]
The FHIT gene was found to span the FRA3B common chromosomal fragile site and aberrant transcripts of the FHIT gene were found in cancer cells [6]
Summary
Despite more than twenty years of research on the WWOX protein, the substrate and product of the enzyme reaction that it catalyses are yet to be discovered. The genes that span them, are part of a protective response mechanism to oxidative stress and likely contributors to the differences seen in aerobic glycolysis (Warburg effect) in cancer cells [32,34] In support of these findings in Drosophila, experiments in human HEK392T cells have demonstrated that WWOX has an interrelationship with metabolism—WWOX is both a regulator of metabolism and is regulated by metabolism [35]. These TNF-mediated cell death phenotypes were shown to correspond to increased levels of reactive oxygen species (ROS), which have previously been shown to be regulated by WWOX [36] Together, these data suggested a protective role for WWOX in the promotion of cell death in response to increased ROS levels, which could correlate with altered metabolism that is observed in cancer. Pathway analysis of WWOX interactors by Lee et al [45] identified a significant enrichment of metabolic pathways associated with proteins, carbohydrates, and lipids breakdown
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