When Good DNA Goes Bad

“Backward” DNA leads to DNA breaks associated with leukemia, study finds

When otherwise normal DNA adopts an unusual shape called Z-DNA, it can lead to the kind of genetic instability associated with cancers such as leukemia and lymphoma, according to a study by researchers at The University of Texas M. D. Anderson Cancer Center.

The study, issued in advance of the Feb. 21 edition of the Proceedings of the National Academy of Sciences, demonstrates for the first time that the oddly shaped DNA can cause DNA breaks in mammalian cells. Interestingly, these sequences prone to forming Z-DNA are often found in genetic “hot spots,” areas of DNA known to be prone to the genetic rearrangements associated with cancer. About 90 percent of patients with Burkitt’s lymphoma, for example, have DNA breaks that map to regions with the potential to form these odd DNA structures.

“Our study shows that DNA itself can act as a mutagen, resulting in genetic instability,” says Karen Vasquez, Ph.D., lead author of the study and assistant professor of carcinogenesis at M. D. Anderson’s Science Park Research Division, Smithville, Texas. “The discovery opens up a new field of inquiry into the role of DNA shape in genomic instability and cancer.”

Imagine untwisting the DNA ladder and then winding it up the other way. The result is a twisted mess with segments jutting out left and right, and the all important base pairs that hold the DNA code zigzagging in a jagged zipper shape. Scientists call this left-hand twist Z-DNA. This is a far cry from the graceful right-hand twisted helix that has become an iconic symbol of biology. It just doesn’t look right, and it doesn’t act right either, according to Vasquez. This awkward shape puts strain on the DNA, and as Vasquez and her colleagues show, can cause the DNA molecule to break completely apart.

Scientists have known for many years that DNA can take shapes other than the typical twisted ladder form, but they weren’t sure how often these alternate shapes occur inside cells.

Researchers who study these shapes had previously shown that Z-DNA can form only at certain DNA sequences because the shapes of the bases themselves contribute to Z-DNA formation. For example, the sequence CG repeated more than 14 times in a row is prone to forming Z-DNA, while the sequence AT is not as efficient at forming this structure. Analysis of the genome reveals that DNA sequences prone to forming the Z-DNA structure occur in 0.25 percent of the genome, according to Vasquez.

She and her colleagues decided to find out whether Z-DNA itself had any effect on the DNA stability. To do that, post-doctoral fellow Guliang Wang, Ph.D., made pieces of DNA designed to form the Z-DNA shape. The researchers then introduced these segments of DNA, called plasmids, into bacterial cells and human cells in the laboratory. They then broke apart the cells and examined what happens to the DNA. They found that in bacterial cells, the Z-DNA caused small deletions or insertions of one or two DNA bases. But in human cells, the introduced Z-DNA led to large-scale deletions and rearrangements of the DNA molecule.

“We discovered that bacterial cells and human cells process the Z-DNA in different ways,” she says. “We aren’t sure why, but we think that the DNA repair machinery may be involved in processing the Z-DNA structure differently in bacteria versus human cells.”

Since formation of Z-DNA is naturally occurring and can exist in the genome, the scientists next want to understand why cells can sometimes process the structure without creating double-stranded breaks. They also want to know why certain places in the genome become “hot spots” for these breaks, while other seemingly similar areas do not.

“If we could understand the players involved in this process, we might be able to prevent the generation of these breaks,” says Vasquez. “For example, if certain types of cell stress lead to breaks, we might be able to find ways to reduce those stresses and prevent breaks.”

Senior research assistant Laura Christensen also contributed to the research. The study was supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences, as well as an Odyssey fellowship to Guliang Wang from M. D. Anderson Cancer Center.