Cell Cycle Inhibition of Silencing in S. Cerevisiae

Purdue University, West Lafayette IN

Investigators

Abstract

Exposure to environmental factors such as viral infection, diet, toxic chemicals and ionizing radiation correlates with altered epigenetic processes in a variety of organisms. Although such factors are implicated in the stably inherited, but inappropriate, expression states of target loci, how such factors affect the regulation of epigenetic processes is poorly understood. The objective of this project is to elucidate how an agent that blocks DNA replication influences the formation of epigenetically inherited structures using silent chromatin in Saccharomyces cerevisiae as a model. Hydroxyurea, a chemotherapeutic agent and an inhibitor of ribonucleotide reductase, was recently shown to prevent a late step in the initial formation of epigenetically regulated silent chromatin at HMR in S. cerevisiae, suggesting that hydroxyurea alters gene expression distal from the site of damage in cis on neighboring regions of the same chromosome. The identification of the mechanism by which hydroxyurea blocks silent chromatin formation will impact our understanding of how conditions that disrupt the cell cycle adversely influence the creation of epigenetically inherited chromatin. In this study, the extent to which events during the hydroxyurea-dependent arrest contribute to this inhibitory signal will be determined by monitoring silencing in mutants that duplicate these events. The source of this inhibitory signal will be identified by mapping analysis and the extent to which hydroxyurea affects histone modifications at HMR will also be determined. To support the scientific education of those beginning their careers in science, both undergraduate and graduate students will help conduct this research as partial fulfillment of their degree requirements. These trainees will have the opportunity to share their findings through presentations at departmental, university-wide and national meetings as well as through publications.