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A powerful genetic model yields insight into cancer cells

Sarah Sabatinos

Chemistry and Biology Professor Sarah Sabatinos, shown in her lab with students, published a study about the division and multiplication of damaged cells. Photo by Christopher Manson.

Researchers at Ryerson University and the University of Southern California have developed a yeast model to study a gene mutation that has been associated with cancer in mice. 

The mutation disrupts the duplication of DNA, causing massive damage to a cell’s chromosomes, while somehow allowing the cell to continue dividing, says a study called “Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast,” in the journal Molecular Biology of the Cell.

The result is a mess: Zombie cells that shouldn’t be able to survive, let alone divide, with their chromosomes shattered and strung out between tiny micronuclei. Sometimes ultrafine DNA bridges connect them to each other. Frequently, the micronuclei — which are thought to retain the most damaged portions of the DNA — rejoin the parent nuclei and incorporate mutations into the survivors.

Lead author Sarah Sabatinos conducted the research as a research associate at the University of Southern California, and is now an assistant professor at Ryerson University in the Department of Chemistry and Biology. “Our work looks at the basic biology of how cells recognize that they are damaged when copying their DNA, and how mutant cells may not get the message to stop. The information we learn about micronucleus formation in yeast will be used in the future to test how human cells develop micronuclei and can help researchers better understand how cancerous cells divide and multiply.”

“Using a simple [non-pathogenic and non-toxic] yeast system, we have developed a powerful genetic model to investigate a recently identified characteristic of human cancer cells,” said Susan Forsburg, senior article author and professor of Biological Sciences at the University of Southern California. “This will enable us to rapidly identify genes responsible for this abnormal division.”

Since the genes that regulate division in human and yeast cells are the same, this simple organism provides a tool for human cell discovery, Forsburg said.

DNA is vulnerable to damage when it’s unzipped into two single strands for replication by a cell’s MCM helicase (a cellular component essential to DNA replication). Typically, the single stranded DNA triggers repair of damage by special enzymes, or — in extreme cases — drives the damaged cell to suicide. Either way, mitosis (cell division) is halted while the issue is dealt with.

But in cancer cells, despite the damaged DNA, the cells continue to divide, creating tumors full of genetic mutations. In this study, a mutation in the yeast’s MCM helicase triggered responses similar to those in mammals where mutations in this gene are associated with cancer and the formation of micronuclei.

To study the phenomenon, Forsburg and Sabatinos collected videos of the damaged cells dividing so that they could maintain continuous monitoring of individual cells, and record cell division from beginning to end. They watched what happened in the mutant in real time. Then, they used a super-resolution microscope that generates 3-D images of objects at the nanometer scale, to examine the damage structures in crisp detail.

“The devil's in the division. In real time, we’re able to see that these mutant cells ignore the damage caused during DNA replication, which results in the creation of unusual structures like micronuclei,” said Sabatinos.