Above: A time-lapse video of cells, imaged to display a single strand of DNA (light blue) and DNA breaks (yellow) during drug treatment.
Certain mutated cells keep trying to
replicate their DNA — with disastrous results — even after
medications rob them of the raw materials to do so, according to new
research from USC.
New imaging techniques allowed
scientists to see for the first time that while chemotherapy drugs
shut down the DNA replication process of most cancer cells, so-called
"checkpoint mutants" just keep chugging along, unwinding
the DNA and creating damaged DNA strands that can result in the kind
of abnormalities seen in cancer cells.
"Older methods suggested that these checkpoint mutants stopped replicating and that the replication machinery simply fell apart to cause DNA damage," said Susan Forsburg, professor of molecular biology at the USC Dornsife College of Letters, Arts and Sciences. "Our new technique suggests that replication processes continue and actively contribute to the damage."
Forsburg is the corresponding author on
a paper about the discovery that was published online in Molecular
& Cellular Biology in October. She collaborated with lead
author Sarah Sabatinos, a postdoctoral research associate at USC, and
Marc Green, a research technician.
The team used a common chemotherapy
drug to put stress on fission yeast cells while they were going
through the DNA replication process. The drug starves cells for
nucleotides, which are the molecules that cells use to build DNA
strands.
Previous studies showed that normal
cells recognize the loss of nucleotides and stop trying to replicate
their DNA — similar to how a driver who runs low on gas stops
before he runs the engine dry.
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."
The next step will be to determine what
happens to the small fraction of mutant cells that survive this
treatment.
"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 chemotherapy," he said.
Contact: Robert
Perkins
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