Some cells don't know when to stop

November 19, 2012


New imaging techniques allowed scientists to see for the first time that while shut down the DNA replication process of most , so-called "checkpoint " just keep chugging along, unwinding the DNA and creating damaged that can result in the kind of abnormalities seen in cancer .

"Older methods suggested that these checkpoint mutants stopped replicating and that the replication machinery simply fell apart to cause ," said Susan Forsburg, professor of at the USC Dornsife College of Letters, Arts and Sciences. "Our new technique suggests that replication processes continue and actively contribute to the damage."


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A time-lapse video of cells, imaged to display a single strand of DNA (light blue) and DNA breaks (yellow) during drug treatment



What the researchers found is that the checkpoint mutants ignore this signal. Using the metaphor above, the driver of the car can't take his foot off of the accelerator and keeps going until his engine sputters to a stop. While this won't necessarily damage a car engine, it's catastrophic for DNA.

These mutant cells keep trying to replicate their DNA, unwinding the strands, until the DNA strands reach a "collapse point" where they break—arguably the worst kind of damage that can be done to a cell.

"We predict that this is a source of increased cancer risk in human cells that harbor checkpoint mutations," Sabatinos said. "Replication-fork instability or collapse may occur at a low frequency in these mutated cells without drug treatment, leading to more frequent DNA changes down the road."


"By bringing to bear a sophisticated combination of genetic tools, drug treatment and state-of-the-art imaging, Susan Forsburg and her co-workers have elicited a fresh perspective on a long-standing problem," said Michael Reddy, who oversees DNA replication grants at the National Institutes of Health's National Institute of General Medical Sciences, which funded the work.

"Their fundamentally revised scenario of the dynamics of fork collapse is likely to lead to invaluable insights as to how checkpoint-defective human cancer cells preserve their DNA, thereby resisting ," he said.

Provided by: University of Southern California

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