Studying the relationship between DNA replication and tandem repeat instability

DNA replication is an essential process for the growth and proliferation of all living organisms. During DNA replication, tandem repeat regions in the eukaryotic genomes must be replicated accurately to prevent their instability leading to repeat expansion or contraction. Tandem repeat instability is associated with various neurological diseases and their accurate duplication during DNA replication is of utmost importance. Currently, little is known regarding the interplay between the DNA replication machinery, termed the replisome, and tandem repeat sequences. Our research proposal is aimed to address fundamental questions regarding the link between DNA replication and tandem repeat instability. To address these questions, we will combine a variety of research approaches including genetics, cell biology and live-cell microscopy. Specifically, we will utilize a novel system for following DNA replication through tandem repeat regions in live yeast cells. We will generate a series of mutant strains by inactivation of key replication proteins to examine the effect of these mutations on replication progression and tandem repeat instability. In addition, we will alter the level and balance dNTPs in the cell that are the building blocks for DNA duplication. Overall, our study will significantly deepen our understanding on DNA replication through repeat sequences and reveal how replication affects tandem repeat instability that is a hallmark of neurological diseases.