DNA Replication and Genome Integrity

All eukaryotic organisms have evolved an organized process of cell division, which enables the genetic information to be accurately copied and distributed to the daughter cells. The process of duplication of the genetic material is called DNA replication. During each cell cycle several hundreds to thousands of replication origins on several chromosomes are activated resulting in the accurate duplication of several million bases of DNA, once and exactly once. Any errors in copying even a single base can be mutagenic and potentially detrimental to the organism. To ensure high fidelity execution of such a complex task, this process is highly regulated both at the cellular level as well as at the level of individual origins on chromosomes.

Lesions in DNA, which arise from exogenous (for example UV radiation) and intrinsic sources (for example free radicals), can compromise the integrity of genetic information and cause cell death. The process of replication is especially vulnerable to these lesions, since it relies on an intact template DNA strand. Cells have therefore evolved checkpoint mechanisms, which respond rapidly to the presence of DNA lesions and replication problems and lead to the adjustment of the DNA replication program, adding a further layer of regulation.

Our lab uses the budding yeast as a model system to understand how these highly conserved processes are interrelated. Yeast offers the advantage of using elegant genetic tools in combination with quantitative biochemical methods and modern genomic and proteomic approaches to elucidate the components of these pathways and their mechanism of action. We study two related aspects of DNA replication. One part of our research focuses on the mechanistic understanding of how post-translational protein modifications such as phosphorylation and ubiquitylation regulate DNA replication during an unperturbed cell cycle. In addition, we study the relationship between DNA replication and the checkpoint in the context of DNA damage.