Inositol polyphosphates: Investigation of their function in the replicative stress response in Saccharomyces cerevisiae.

Abstract

Inositol polyphosphates (IPs) represent an ubiquitous class of highly charged, water-soluble molecules conserved from yeast to humans, playing fundamental roles in cellular homeostasis and implicated in human diseases such as diabetes and cancer. Despite their greater diversity compared to lipid phosphoinositides, IPs remain less characterized. In recent years, attention has been focused on elucidating the relationship of IPs with nuclear processes such as gene expression regulation, telomere maintenance, mRNA export, DNA replication, and repair. Interestingly, we have shown that deletion of different inositol polyphosphate kinases (IPKs) leads to a hypersensitivity phenotype to hydroxyurea (HU), an inhibitor of dNTP synthesis, which may indicate that IPs play a crucial role in the response to replicative stress and, consequently, in maintaining genomic stability. Therefore, this research project aims to characterize the role of IPs in the response to HU-induced replicative stress and their potential modulation of DNA damage signaling pathways mediated by Mec1 and Rad53 kinases (ATR and CHK1/2 in humans). Since IPs are molecules present in all eukaryotes and replication stress is closely associated with tumorigenic processes, the results obtained in this research project could be relevant to deepen the understanding of mechanisms for maintaining genomic integrity in eukaryotes.