July 1, 2003

It sounds like one of those too-good-to-be-true advertisements in a health magazine: â??Common bakerâ??s yeast from your kitchen cabinet could hold the key to curing cancer.â?

Yet, a researcher whose work could be titled just that has recently joined UNT Health Science Centerâ??s Department of Cell Biology and Genetics.

Wolfram Siede, PhD, a cell biologist who previously worked at the Emory University School of Medicine, is using common yeast to seek answers to how human cells defend against and repair cancer-causing damage to DNA caused by environmental stress. His latest study is part of a National Institute of Environmental Health Sciences multi-study project funded at $1.2 million a year for five years.

Dr. Siedeâ??s team is one of five separate but collaborative initiatives, each investigating a different aspect of DNA repair, damage tolerance and damage prevention in response to exposures to radiation or chemical agents that can corrupt cellular DNA.

Why yeast? Because it is a single-cell model organism of simple structure, and its DNA sequence was already determined several years ago, Dr. Siede said. Since yeastâ??s basic genetic mechanism is just as complicated as cells found in humans, researchers can conduct experiments in a stage that human cell research will not reach for another 10 years.

â??The motor or origin of cancer is genetic instability. Control processes are inactivated and cells canâ??t maintain their genetic makeup,â? he said. â??By investigating yeast at the basic level that is the same in all cells, we can see what happens when the genetic makeup is being challenged. Because yeast is such a convenient system, we can get results quickly and donâ??t have many additional factors to consider like in human studies.â?

Dr. Siede said any organism, whether as simple as yeast or as complicated as the human cell, has to deal with external genotoxic stressors such as ultraviolet light, chemical agents and radiation in addition to the daily barrage of internal physical insults produced by normal cellular metabolism. Damage by genotoxins changes the chemical structure of DNA components, setting the stage for biological consequences such as cell death, cell mutation and the development of cancer. Dr. Siede said learning the process and points in the cellâ??s life cycle where these changes occur will contribute to scientistsâ?? understanding of how cancerous cells develop in humans.

Progress in the research by Dr. Siede and others in the field has shown a lot about the mechanisms related to yeastâ??s reaction to DNA stressors, and now his research has evolved to look at how the cell regulates DNA repair.

One major topic of his research is regulation of DNA damage tolerance. â??Cells have a way of tolerating the damage and delaying repair. Thatâ??s okay for a simple cell like yeast â?? itâ??s a way for them to just go on with life. However, in an organized tissue of human cells, the damage builds up until it puts cells at risk of not being able to do DNA repair. It doesnâ??t make a lot of sense for cells to tolerate the damage, but they do.â?

The tolerance aspect is a new concept in the study of genotoxic damage, and it has researchers questioning how it fits into the human model. Dr. Siede said the current thinking is that regulation is a key for when it invokes the tolerance, for when the cell determines the benefit of tolerating damage is greater than the risk, but it is unclear at this point just when and why that happens.

Another area of interest concerns cell cycle regulation. As early as 1987, researchers realized that if one damages the DNA in cells, the cells will stop their cycle because they need time for repairing. Dr. Siede explained that it is at certain points in a cellâ??s cycle progression, called checkpoints, that a cell is able to arrest its cycle in response to DNA damage. Such checkpoints are essential to preserve genetic stability.

Of concern is when a cell is not triggered at its checkpoint and is exposed to deleterious aspects of unrepaired DNA damage rather than stopping the cycle for repair. These checkpoints are frequently defective in tumor cells â?? but why?

â??Many people think that is why they are cancer cells,â? Dr. Siede said, â??because of that defect in a very early step of a process that maintains genetic stability.â?

Another project related to his work in checkpoint regulation won him a RO1 level award â?? the best you can get â?? from the National Institutes of Health. Dr. Siede is using yeast to develop a short-term model for certain aspects of checkpoint activation that can be used for screening anti-cancer agents.

â??Agents that activate the checkpoints in normal cells but not in cancer cells represent a window of opportunity for treating cancer, and agents that actually modify the checkpoint response are of considerable interest in cancer therapy,â? he said.

â??The chemical industry can provide many new agents for fighting cancer,â? Dr. Siede said, â??but all have to be tested. In an early stage, yeast can be used for those tests.â?

Prior to his position at Emory University as an assistant professor in the Department of Radiation Oncology and with the Winship Cancer Institute, Dr. Siede was an instructor and research assistant professor at the University of Texas Southwestern Medical Center at Dallas. He received his doctorate degree in microbiology from the J.W. Goethe University in Frankfurt, Germany, before completing post-doctoral work in molecular biology at Stanford University School of Medicine.

Dr. Siede co-authored a textbook, DNA Repair and Mutagenesis, with mentor Errol Friedberg, MD, of UT Southwestern and Graham Walker, PhD, of MIT.

In addition to his research, Dr. Siede teaches courses in cell regulation and DNA repair for the health science centerâ??s Graduate School of Biomedical Sciences.

â??I came to the health science center for several reasons, but foremost because I see an opportunity to make a difference in an up-and-coming research institution. There are many benefits to being here. Good graduate students, the advantages of being at a smaller institution, friends I have in the area, the location of the campus in a world-class arts district â?? there were so many factors that made up my decision.â?


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