Our goal is to uncover novel biological functions and potential medical application of Piwi (P-element induced wimpy testis in Drosophila) proteins. Piwi proteins and piRNAs (Piwi-interacting non-coding RNAs) constitute a molecular machinery, the Piwi-piRNA pathway, the primary function of which is to repress the activity of mobile genetic elements (MGEs), also called “jumping” genes. Jumping into a novel genomic locus, active MGEs can generate insertional mutations in functional DNA regions (these mobile DNA stretches are termed as biological mutagens), hence the operation of the Piwi-piRNA pathway is essential for maintaining genomic stability. This is particularly important in the light of the fact that almost half of the human genome consists of MGE-derived repetitive elements. Interestingly, the activity of the Piwi-piRNA pathway, which was originally identified in the non-aging germline connecting genetically the subsequent generations, has been widely observed in cancerous cell lines and in somatic stem cells of certain lower ranked animal species such as the freshwater hydra and flatworm planaria. Thus, the activity of Piwi proteins exclusively characterizes the non-aging cells exhibiting an unlimited proliferation capacity. These proteins may have a substantial role in inhibiting the aging process (e.g. germline immortality), and conferring replicative immortality for cancer stem cells. According to our approach, a cancerous cell is capable of inducing tumor growth when it ectopically expresses Piwi proteins (so, it behaves similar to germline cells). In the frame of this project we intend to downregulate Piwi proteins, in particular the four human paralogs (PIWIL1-4), in cell cultures, and also in animal (Drosophila) models of cancer, as well as hyperactivate these proteins in animal genetic models. The effect of these genetic interventions on tumor development will be examined. Genetic inactivation/downregulation of Piwi proteins, leading to a significant level of genomic instability in the affected cells, may inhibit proliferation/survival in cancerous cells, while somatic (ectopic) expression of Piwi proteins may slow down the rate at which cells age, thereby extending lifespan. We also wish to identify proteins and RNAs that interact with Piwi proteins, and study the genetic control of Piwi expression.

Tamás Orbán, Tibor Vellai

Result_May 2020