Backward DNA Linked to Leukemia, Lymphoma

Mutated Structure Causes Breaks That Lead to Cancer

When otherwise normal DNA adopts a "backward" shape called Z-DNA, it can lead to the kind of genetic instability associated with cancers such as leukemia and lymphoma, according to new study results.

The study, published in 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.

These breaks, or sequences, often are found in genetic "hot spots," areas of DNA known to be prone to genetic rearrangements associated with cancer. About 90% of patients with Burkitt's lymphoma, for example, have DNA breaks that map to regions with potential to form non-canonical DNA structures (e.g. H-DNA or Z-DNA).

Scientists hope that further study eventually could lead to methods of preventing the breaks, thus preventing the development of cancer, 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.

Unusual shape strains DNA, spurs cancer growth

To get an idea of what Z-DNA looks like, imagine untwisting the DNA ladder and then winding it up the other way. The result is segments jutting out left and right, and the all-important base pairs that hold the DNA code zigzagging in a jagged zipper shape.

The structure is a far cry from the graceful right-hand twisted helix of normal DNA that has become an iconic symbol of biology. The awkward Z-DNA shape puts strain on DNA, the material inside cells that carries genetic information responsible for growth and development. As Vasquez and her colleagues show, Z-DNA 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 were not sure how often these alternate shapes occur inside cells.

Study serves as foundation for future research

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. Analysis of the human genome (the complete set of genes for each person) reveals that DNA sequences prone to forming the Z-DNA structure occur in 0.25 percent of the genome, Vasquez says.

Since formation of Z-DNA is naturally occurring, 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," Vasquez says. "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."