Research Program: Genetic Mechanisms of Cancer
Associate Professor, Department of Genetics, Cell Biology, and Development

dkirkpat@umn.edu
612-624-9244- office
612-625-4740 — lab
Preferred method of contact: e-mail

Dr. Kirkpatrick received his Ph.D. in 1994 from MIT, where he worked in the laboratory of Dr. Frank Solomon in the Center for Cancer Research, investigating microtubule formation in the yeast Saccharomyces cerevisiae. Upon graduation, he joined Professor Tom Petes' research group at the University of North Carolina, Chapel Hill, as a postdoctoral researcher investigating DNA repair and recombination during meiosis. He established his own research group at the University of Minnesota in 2000, focusing on the role of DNA repair in genome stability in Saccharomyces cerevisiae and Candida albicans.

Research Interests

The Kirkpatrick lab is interested in understanding the mechanisms of DNA repair, and the cellular processes in which they are involved, using the yeasts Saccharomyces cerevisiae and Candida albicans.

Minisatellite DNA stability: Repetitive DNA sequences are much more unstable than unique DNA sequences, and many human diseases, including cancers, have been associated with instability of repetitive DNA tracts. We are investigating the factors, both genetic and structural, that control the stability of repetitive minisatellite DNA sequences. Using a yeast model system in which a minisatellite associated with the human HRAS1 oncogene has been inserted into the S. cerevisiae genome, we demonstrated that the HRAS1 minisatellite tract undergoes length alterations and rearrangements during meiosis, and that genes involved in meiotic recombination and DNA loop repair are required for tract stability. We also showed that the structural factors of the minisatellite that influence stability include the total length of the tract, and the degree of sequence variation within the tract. Recently we have determined that the stability of minisatellite tracts is highly regulated while cells are arrested in stationary phase, and is dependent on recombination proteins and zinc homeostasis. As the vast majority of cells in the human body are in stationary phase, these results open up a brand new avenue of research. Alterations in the HRAS1 minisatellite tract in humans have been correlated with various cancer susceptibilities; determination of the components responsible for these alterations will be important in understanding the etiology of these diseases.

Meiotic DNA Repair in S. cerevisiae: Recombination is an essential process during meiosis that generates diversity, ensures the proper segregation of chromosomes, and acts to repair DNA damage. Three repair pathways have been identified genetically for meiotic mismatch repair: the first pathway is responsible for base-base mismatches, while the second and third are required for repair of large loops. Mutant screens to identify novel genes that are involved in these repair pathways are being conducted. Three different screens are ongoing or in the process of being set up—a mitotic screen based on loop repair within the ADE2 gene, a screen based on loop repair during meiosis, and a collaboration to screen all of the deletions of the non-essential genes in the S. cerevisiae Yeast Deletion Strain Bank.

DNA Repair Pathways in C. albicans: Candida albicans is a commensal organism in humans, but is also an opportunistic pathogen, especially in immunocompromised individuals. We have demonstrated that DNA Double-strand Break Repair (DSBR) and Mismatch Repair (MMR) are involved in the acquisition of resistance to antifungal drugs by Candida. The long-term goal of this project is to identify the complete complement of cellular DNA repair factors that act on the genome of Candida, and the role that those factors play in the acquisition of antifungal drug resistance by the yeast, to aid in drug design and improve patient recovery percentages.

Selected Publications

Legrand M, Forche A, Selmecki A, Chan C, Kirkpatrick DT, Berman J. Haplotype mapping of a diploid non-meiotic organism using existing and induced aneuploidies. PLoS Genetics 2008;4:e1.

Kelly MK, Jauert PA, Jensen LE, Chan CL, Truong CS, Kirkpatrick DT. Zinc regulates the stability of repetitive minisatellite DNA tracts during stationary phase. Genetics 2007;177:2469-2479.

Legrand M, Chan CL, Jauert PA, Kirkpatrick DT. Role of DNA mismatch repair and double-strand break repair in genome stability and antifungal drug resistance in candida albicans. Eukaryotic Cell 2007;6: 2194-2205.

Jensen LE, Jauert P A, Kirkpatrick DT. The large loop repair and mismatch repair pathways act on distinct substrates during meiosis. Genetics 2005;170:1033-1043.

Jauert PA, Kirkpatrick DT. Length and sequence heterozygosity differentially affect HRAS1 minisatellite stability during meiosis in yeast. Genetics 2005;170: 601-612.

Borts RH, Kirkpatrick DT. The Role of the Genome in Meiotic Recombination. In: The Implicit Genome, editor: Lynn Caporale 2005.

Jauert PA, Jensen LE, Kirkpatrick DT. A novel yeast genomic DNA library on a geneticin-resistance vector. Yeast 2005;22:653-657.

Sia EA, Kirkpatrick DT. The yeast MSH1 gene is not involved in DNA repair or recombination during meiosis. DNA Repair 2005;4:253-261.