The role of inositol metabolism and its phosphorylate derivatives in the response to genomic damage in Saccharomyces cerevisiae

Abstract

The DNA Damage Response (DDR) contribute to genomic stability through the modulation of a myriad of cellular pathways that are responsible to detect DNA lesions, promote DNA Damage signaling and active DNA repair and DNA damage tolerance mechanisms. Besides that, it also modulates another cellular responses such as protein homeostasis and metabolism of biomolecules such as carbohydrates and lipids. In the budding yeast Saccharomyces cerevisiae, the DNA Damage signaling is coordinated by the PI3KKs (phosphoinositide 3 kinase-related protein kinases) related kinases Mec1 and Tel1 (ATR and ATM in humans) and by the downstream kinase Rad53 (related to CHK1 and CHK2 in humans). These kinases are responsible to sense the DNA Damage and transduce the signal through the phosphorylation of several protein targets leading to several biological responses such as cell cycle arrest and inhibition of DNA synthesis avoiding cytokinesis in the presence of DNA lesions, and consequently genomic instability. In the last two decades, the mechanisms responsible for the regulation of these kinases have been extensively studied. Interestingly, it has been postulated that inositol related molecules have the ability to modulate the DDR, but the mechanism behind this regulation is still unknown. Therefore, this project sought to study the role of the inositol metabolism for the modulation of the DDR and maintenance of genomic stability. Because the metabolic pathways involved in this project are conserved form yeast to humans, the results obtained in this study have the potential to be validated in mammalian cells, thus potentially contributing for the understanding of several diseases such as Cancer. (AU)