WWOX and DNA Damage: A Potential Role in the Regulation of Oxidation-Induced Signaling Pathways

One of the known hallmarks of cancer is genome instability. Through a variety of DNA damage response (DDR) mechanisms, the genome is able to maintain its integrity upon exposure to different stresses such as ionizing radiation, UV, replication, oxidative stress, etc.
The WW-domain containing oxidoreductase (WWOX) is a tumor suppressor whose absence has been implicated in most common cancers. WWOX spans the common fragile site FRA16D and contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. Through its protein-protein interactions, WWOX regulates the function of many signaling proteins and is involved in regulating different cellular pathways. WWOX has previously been shown to have a direct connection with DNA damage repair.
In order to further uncover WWOX`s involvement in DDR, we preformed mass spectrometry analysis on immunopercipitated WWOX, focusing on the differences in binding repertoire before and after inducing DNA damage. We identified proteins that are known to be involved in oxidation-induced DNA damage. In addition, we identified Thioredoxin, a multifunctional protein involved both in maintaining the redox state of the cell and in signaling. Given that WWOX has an oxidoreductase domain, our main objective is to identify the role of WWOX in regulating the repair of oxidation-induced DNA damage and its effect on levels of ROS necessary for signaling and cell death regulation. Understanding of the functional relationship between WWOX and its novel DDR interactors will allow us to further define the role of WWOX in DDR and maintenance of genome stability, as a means for tumor suppression.