When DNA Goes Bad - Leukemia May be the Result

[Guest guest]

When Good DNA Goes Bad

" Backward " DNA leads to DNA breaks associated with leukemia, study

finds

M. D. News Release 02/10/06

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. 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 Vasquez, Ph.D., lead author of the

study and assistant professor of carcinogenesis at

M. D. 's Science Park Research Division, ville,

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 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.

Cancer Center.

©2006 The University of Texas M. D. Cancer Center