UC DAVIS (US) — DNA repair in cancer cells is not a one-way street, according to a new study that clarifies how cancer cells can become resistance to damage-inducing treatments.
“What we discovered is that the DNA repair pathway called recombination is able to reverse itself,” says Wolf-Dietrich Heyer, professor of microbiology and of molecular and cellular biology at the University of California, Davis.
“That makes it a very robust process, allowing cancer cells to deal with DNA damage in many different ways. This repair mechanism may have something to do with why some cancer cells become resistant to radiation and chemotherapy treatments that work by inducing DNA damage.”
The self-correcting ability of the DNA repair system is like driving in a modern city, Heyer says, where U-turns and two-way streets make it easy to correct a wrong turn. “How much harder would it be to re-trace your path if you were in a medieval Italian city with only one-way streets?”
For the current study published online in Nature, Heyer and colleagues used yeast as a model system to clarify the mechanisms of DNA repair. They expect their findings, like most that come out of work on yeast, will be confirmed in humans. “Whether in yeast or humans, the pathways that repair DNA are the same,” he says.
The research team used electron microscopy to observe repair proteins in action on strands of DNA. They saw a presynaptic filament called Rad51 regulating the balance between one enzyme (Rad55-Rad57) that favors recombination repair and another (Srs2) that inhibits recombination repair.
By controlling the balance between the two enzymes, Rad51 can initiate genetic repair—or the U-turn—as needed. “It is a tug-of-war that has important implications for the cell because, if recombination occurs at the wrong time in the wrong place, the cell may die as a consequence,” Heyer says.
The ability of the repair system to abort ill-fated repair attempts, gives the cell a second shot, improving cellular survival after its DNA is damaged—exactly what is dreaded in cancer treatment.
“There are a lot of hints in the scientific literature suggesting that DNA repair contributes to resistance to treatments that are based on inducing DNA damage such as radiation or certain types of chemotherapy,” Heyer says.
“The ability of cancer cells to withstand DNA damage directly affects treatment outcome, and understanding the fundamental mechanisms of the DNA repair systems will enable new approaches to overcome treatment resistance.”
The team’s next step is to look at the enzyme system in humans and see whether they find the same principles at work. One application of this work will be to target the self-correcting mechanism in cancer cells as a way of sensitizing them to radiation and/or chemotherapy treatments.
“If we can confirm that these types of mechanisms exist in human cells, then we will have an approach for making cancer cells more sensitive to DNA damage-inducing treatments.”
The study was funded by the National Institutes of Health, the Tobacco-Related Disease Research Program, the European Community, the French National Centre for Scientific Research, the French Atomic Energy Commission and SystemsX.ch (The Swiss Initiative in Systems Biology).
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