Kristina H. Schmidt

The main goal of my laboratory is to obtain a better understanding of how eukaryotic cells preserve the integrity of their genome. Genetic studies of the yeast Saccharomyces cerevisiae have implicated numerous genes in the maintenance of genome stability, including those that function in cell cycle checkpoints, DNA replication, mismatch repair, recombination, oxidant defense mechanisms and telomere maintenance. Cells with defects in these pathways can accumulate point mutations, frameshifts and/or gross-chromosomal rearrangements, i.e. translocations, chromosome fusions, large interstitial deletions or terminal deletions of chromosome arms that are healed by de novo telomere additions.
Of particular interest to me are S. cerevisiae proteins that function at the interface between DNA replication and DNA repair, such as the non-replicative DNA helicases Sgs1, Rrm3 and Srs2. Cells with mutations in any one of these DNA helicases grow normally and exhibit low to moderate levels of genome instability, whereas mutations in any two of these DNA helicases lead to a severe, slow-growth phenotype that can be suppressed by disrupting homologous recombination. This suggests the accumulation of recombination-dependent DNA structures that cannot be accurately resolved and become toxic to the cell. My current work utilizes a wide range of genetical and biochemical techniques to investigate how these DNA helicases and interacting proteins may aid replication fork progression, prevent the initiation of aberrant recombination events and suppress chromosomal rearrangements.
S. cerevisiae is genetically and biochemically well characterized and its genome is fully sequenced and annotated. Its excellent genetics and ease of manipulation make it one of the most powerful model organisms for the study of evolutionarily highly conserved DNA metabolic pathways. Many of the genes being studied in my laboratory have human homologues, of which some are known to be involved in genetic diseases. Thus, insights gained from our investigations may shed light on the causes of genome instability in human cells, cancer predisposition and aging.