Scientists find unique nuclear DNA structure

May 14, 2000

Shed Light on Antibody Production

For the first time since Watson and Crick described the double helix, a new and unique stable nuclear DNA structure has been discovered and described by scientists at the Keck School of Medicine of the University of Southern California and the USC/Norris Comprehensive Cancer Center.

That unique DNA structure helped the scientists also elucidate for the first time the process by which the different classes of immunoglobulins (also known as antibodies) are produced.

These findings, published in the May 12 issue of the journal Science, may also help researchers better understand how one type of B cell cancer, Burkitt's lymphoma, comes into being. (The B cells are the cells that produce immunoglobulins.)

"The way in which the different immunoglobulin classes are created is a nearly perfect system," noted Michael Lieber, M.D., Ph.D., professor of pathology and biochemistry, and the study's principal investigator. "And yet, the DNA mechanism for how a cell switches from producing one class to producing another has remained a mystery for almost 20 years."

Until now, that is.

"We've discovered that it occurs by forming an unusual structure in the DNA within a chromosome," Lieber said.

Two other unusual structures have been previously described, he explained, but these are short bits of DNA that require other proteins to stabilize them. The structures being described in the Science article are long regions of DNA, and they are intrinsically stable; they don't require any outside proteins to hold them together.

The typical antibody molecule is shaped like the letter Y. The region at the end of each of the two short protein arms houses the receptors that recognize and bind with a specific foreign object, or antigen, while the long stem, or handle, determines to which immunoglobulin class the antibody belongs.

An immunoglobulin's class is important because it determines where in the body the antibody's efforts will be concentrated. And so, while immunoglobulin M (IgM) works mostly in the bloodstream, IgG, for instance, can easily slip through a capillary's walls and cross a placenta, and IgA is at home in the lungs, the digestive tract and the body's secretions - saliva, sweat and tears.

Switching from one class to another requires a change in the immunoglobulin's "handle." By undergoing this so-called class switch, the body can send "the same antibody missile to different areas of the body," Lieber explained.

By studying the process of class switching in B cells from a mouse's spleen, Lieber and Keck colleagues Robert B. Tracy, Ph.D., research associate in pathology, and Chih-Lin Hsieh, Ph.D., associate professor of urology and biochemistry and molecular biology, found that class switching involves a cutting and joining process in which the RNA strand decoding the DNA instructions "gets stuck between two strands of DNA, creating what is called an R loop," Lieber said. "These layers look a bit like a sandwich." (Tracy and Lieber described the precise structure of this R-loop in the March 1 issue of the EMBO Journal.)

That circular sandwich is transient. Eventually, the loop is snipped off and set aside, while the ends of the two remaining strands are rejoined. But the effects are long-lasting. This cutting and pasting - known as a recombination event - cannot be undone. Once a cell decides to make, for example, IgA, it must clip out the instructions for IgE, IgG and IgM. Afterwards, it can make nothing but IgA.

"In general, DNA is a stable blueprint," said Lieber. "Class switching is one of only two processes that alter the DNA blueprint in the nucleus - one of only two DNA-cutting and - joining processes in all animal cells." The other nuclear recombination event is closely related - the process that creates the antigen-binding pockets topping the short arms of the immunoglobulins.]

"We've identified a structure integral to part of the immune system, and we've detailed how it develops," said Tracy, the paper's lead author.

Now, he added, the next step is to try to tease out the nuclear enzyme, or nuclease, that actually does the cutting of the unique looped structure.

"Finding that will be critical for a detailed understanding of the whole mechanism," he said.

A detailed understanding of this immunologic mystery may also provide clues to just how Burkitt's lymphoma, a type of non-Hodgkin's lymphoma, gets its start in the human body.

It turns out, Tracy said, that when immunoglobulin class switching does not occur correctly, it can set off a chain of events that can lead to a swapping of genetic material between two chromosomes - the one containing the class-switching genes and the one on which a known cancer-causing gene resides. That translocation, as it's called, can activate the cancer-causing gene, prompting unchecked cellular division.

"If we can figure out how class switching normally works," says Tracy, "we can also begin to figure out why this cancer occurs."
The USC research was supported by National Institutes of Health grants and a Bank of America fellowship.

EDITOR: See Robert B. Tracy, Chih-Lin Hsieh, Michael R. Lieber, "Stable RNA/DNA Hybrids in the Mammalian Genome: Inducible Intermediates for Immunoglobulin Switch Recombination" in Science, 12 May 2000.

University of Southern California

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