Structural and functional analysis of human PIWI proteins
Age is a significant risk factor for developing cancer; the older a person, the higher her/his chance to develop a tumor. Hence, cancer and aging may be genetically intertwined processes. One of the major hallmarks of cancer stem cells underlying tumor growth is replicative immortality, the basis of which may be provided by genomic integrity. Similar to germline stem cells, cancer stem cells thus belong to the class of non-aging cells. Each tumorous cell line investigated so far to this feature has been proven to be positive for the ectopic accumulation of PIWI (P element-induced wimpy testis in Drosophila) proteins. Through inhibiting the activity of mobile genetic elements (“jumping genes”) generating insertional mutations, thereby leading to a significant level of genomic instability at advanced ages, PIWI proteins play a key role in ensuring the genetic stability of non-aging cells. According to our hypothesis, the replicative immortality of cancer stem cells results from the activity of PIWI proteins, therefore these proteins can be used as potential targets for drugs with anti-cancer effects and early markers for cancer. The aim of our project is to express the human PIWI proteins (PIWIL1-4) in a baculovirus system. Using PIWIL proteins, we wish to develop PIWIL-specific functional tests. These tests help identify specific PIWIL-blocking small molecules (drug candidates) with potent antitumor effects. Structural characterization of PIWIL proteins can lead to the in silico identification of specific PIWIL-interacting molecules. The long-term goal of our project is to determine and analyze new generation (PIWIL-inhibiting) drug candidates with antitumor effects.
Tibor Vellai, András Málnási-Csizmadia