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International Team Maps Genetic Interactions in DNA-Damaged Yeast Cells

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Genetic interactions in eukaryotic cells shift dramatically in response to DNA damage, a new yeast study suggests.

An international research team used an approach dubbed "differential epistasis map" to catalog the changes in genetic interactions that occur when yeast DNA is damaged, evaluating tens of thousands of double mutant yeast cell lines before and after the cells were treated with a DNA-damaging drug.

The study, which appeared online today in Science, shows that it's possible to "map how genetic networks in cells are reprogrammed in response to stimuli, thus revealing functional relationships that would go undetected using other approaches," co-corresponding author Trey Ideker, division of medical genetics chief at the University of California at San Diego School of Medicine, said in a statement.

Genetic interactions can provide a window into the function of genes and proteins, the researchers explained, uncovering situations in which genes influence one another or contribute to common or redundant processes.

Early this year, for example, a University of Toronto-led team reported in Science that they had used a synthetic genetic array strategy to map genetic interactions across the yeast genome, incorporating additional data on chemical-gene interactions.

Nevertheless, Ideker and his co-authors noted, large genetic interaction networks are typically constructed under normal laboratory circumstances when cells are not exposed to external stressors.

In an effort to develop a more dynamic understanding of genetic interactions in yeast cells, the researchers used Saccharomyces cerevisiae cell lines containing mutations or deletions in 418 genes involved in a range of process — from cell signaling and transcription to DNA repair.

The team then assessed roughly 80,000 double mutant yeast strains containing mutations in these genes, looking at which mutation combinations led to altered or impaired growth in the presence or absence of a DNA-damaging compound called methyl methane-sulfonate (MMS).

In the process, the researchers found 2,297 genetic interactions in the DNA damaged yeast — a few hundred more than the 1,905 interactions found in cells grown under typical conditions.

In each network, the team identified genetic interactions that coincided with known physical interactions between corresponding proteins, consistent with the idea that genetic networks can provide a peek into gene function.

Even so, the nature of the genetic interactions detected varied substantially between cells grown under normal laboratory conditions and those exposed to MMS.

Overall, the researchers identified 873 interactions that differed between the networks, including 379 interactions associated with poorer growth under DNA-damaging conditions and 494 interactions that apparently represent examples of "inducible epistasis" — genetic interactions that reduced the toxicity to the cells with damaged DNA.

By bringing together and comparing groups of genes that clustered together under normal circumstances and in response to DNA damage, the team defined dozens of interacting gene groups as well as groups of these so-called gene modules that interact with other modules.

Such shifting interactions support the notion that "network comparison reveals a landscape of genetic interactions particularly tailored to the cellular response of interest," the authors explained.

Moreover, the team's genetic interaction data offered clues to previously unknown functions for certain proteins. For instance, they reported, interactions involving a gene coding for the kinase Slt2 hint at an unappreciated roles for the protein in DNA repair in S. cerevisiae.

The extent of the genetic network rearrangements in yeast also suggests additional research is needed to understand the sorts of gene and protein interactions that exist in other eukaryotic cells, including human cells, under different environmental conditions.

"The Human Genome Project has identified 30,000 genes and their sequence variants across different individuals," Ideker noted. "However, it leaves completely unanswered how these different genes interact to form the molecular machines that run the cell and govern its various responses. We now have the parts list, but we also need to understand the network connecting all of these parts, and how to fix it during disease," he said.

"As we look to extend this approach to mammalian systems and ultimately to human cells, new challenges will arise — the ability to selectively control the genetic makeup of cells, the redundancy in genes, transcription factors, and other molecules that make more advanced systems more robust, but also more complicated to study," National Institute of Environmental Health Sciences Program Officer David Balshaw, who was not directly involved in the research, added in a statement.

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