We study how cells respond to and repair DNA damage, and how it impacts genome stability. Cells sustain thousands of DNA lesions every day from internal sources, including oxidative damage, replication errors and replication fork collapse, and from outside sources such as radiation and chemical agents. DNA damage and the resulting defects in DNA replication are a major source of genetic rearrangements that can cause diseases including cancer and aging. Additionally, DNA damaging agents see considerable use as therapeutics, particularly in cancer treatment. We combine high-throughput screens for global identification of genes and pathways that contribute to the DNA damage response with detailed molecular biological and biochemical analysis of pathway components in order to understand how cells respond to and repair different types of DNA damage.
We use the budding yeast Saccharomyces cerevisiae, as well
as mammalian cells, as models in which to study
DNA replication, the DNA damage response, and genome instability. Genetic studies of
the cell cycle in yeast have identified many proteins involved in
regulating progression from G1 phase into S phase, proteins involved
in the DNA damage response, and proteins important for genomic stability.
The highly conserved nature of these processes makes study of the
yeast cell cycle directly relevant to higher eukaryotes, including
humans. The ease of genetic manipulation in yeast makes this model
systems ideal for introducing changes into proteins and examining
the effects of these changes on cellular processes. Functional genomic
and proteomic approaches are well established in yeast and provide
a means of studying these processes on a genome-wide scale.