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Janet E. Lindsley

Associate Professor of Biochemistry

B.S. Davidson College

Ph.D. University of Wisconsin, Madison

Research

References

janet.lindsley@hsc.utah.edu

Janet Lindsley's Lab Page

Research

Chromosomes must be both dynamic and stable during the life of a cell. They must be dynamic in their responses to transcriptional regulation, replication, repair, condensation and mitotic segregation. However, the genetic information must also be stably maintained during these processes. My laboratory is studying two aspects of this dichotomy: mitotic chromosome condensation and chromosome translocations. Additionally, we have an ongoing interest in the mechanism of DNA topoisomerases, and how these enzymes are involved in both condensation and translocations.

At the onset of mitosis, chromosomes condense. Genetic and biochemical evidence indicates that a conserved complex of five proteins, the condensin complex, is required for this process. Two proteins in this complex, Smc2p and Smc4p, are predicted to be the motor proteins that couple the chemical energy released from ATP hydrolysis to the mechanics of chromosome condensation. We are studying the yeast condensin complex, utilizing the powerful biochemistry and genetic techniques available for this organism. Our goal is to understand the mechanism by which this complex utilizes ATP to condense chromosomes. With the entire complex over-expressed and purified, we are presently using a combination of structural, kinetic, mutational and DNA topological studies to probe its mechanism.

Chromosome translocations are a form of genome instability found in many types of cancer. Simple, non-random translocations are often causal events in the development of leukemias and lymphomas, while complex, random translocations are found in many solid tumors. Apart from translocations found in a subset of lymphoid tumors that most likely involve the RAG recombinase, very little is known about the mechanisms underlying the generation of chromosome translocations. One consistent feature of translocations is the division of genetic material originally present on one chromosome onto separate derivative chromosomes. The goal of this project is to study how translocations occur by using this principle in a novel genetic selection system in yeast (see figure). A yeast artificial chromosome, the translocation YAC, was designed to have positive selection markers at one end (green) and negative selection markers at the opposite end (red). A segment of human DNA (blue) lies between these markers. A translocation breakpoint that falls within the human DNA will place the positive selection markers on a separate derivative chromosome from the negative selection markers. The derivative YAC is destabilized by inactivating its conditional centromere. Therefore, even very rare translocation events can be detected by selecting for the stable presence of the positive selection markers and the loss of multiple negative selection markers. We have recently shown that this selection system is highly effective; 98% of cells selected contain chromosome translocations. We are presently using this system to study which gene products, environmental factors and DNA sequences contribute to the production or prevention of chromosome translocations.

A novel genetic selection system for chromosome translocations in yeast. See text for details.

References