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.
University of Southern California: http://www.usc.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
From Dr Strangelove and water fluoridisation to climate change, scientific method and facts are not always enough to win over the sceptics
On a blog post at PLOS, the tropical disease expert Peter Hotez and postdoctoral fellow Jennifer Herricks take a run through the data on the biggest killers of children around the world in 2013, part of a new dataset from Global Burden of Disease study published in the January Lancet.
Tory MP David Tredinnick seems to believe that astrology could inform and improve UK healthcare. This view is misguided and potentially dangerous
Resistance to vital antimalarial drugs called artemisinins has spread across Burma to the Indian border. If not contained, it could ultimately hit Africa hard
Clostridium difficile sickens nearly half a million Americans annually, killing about 29,000, say federal health officials. They warn hospitals and nursing homes to tighten hygiene protocols.
Study looking at transmission among men who have sex with men recruited 545 participants at high risk of contracting HIV A daily pill can effectively protect gay men against infection with HIV
An experimental therapeutic vaccine from Danish drugmaker Bavarian Nordic helped significantly extend survival in patients with advanced prostate cancer, according to results of a small early-stage trial conducted by the U.S. National Cancer Institute.
Scientists interviewed more than 1,000 men, women and children who were forced into sex work and hard labor. The result is the largest study to detail the health of human trafficking survivors.
Gerbils from Asia rather than black rats were responsible for repeated outbreaks of the bubonic plague in Europe, a study suggests.
The so-called "cuddle-chemical" seems to block the action of alcohol in the brain, preventing the tell-tale signs of drunkenness in rats