As a general rule, your DNA is not something you want rearranged. But there are exceptions 鈥� especially when it comes to fighting infections. Since the number of microbes in the world far surpasses the amount of human DNA dedicated to combat them, specialized cells in the immune system have adopted an ingenious, if potentially disastrous, strategy for making antibodies. These cells, called B lymphocytes, intentionally mutate their own DNA to ward off invaders they have never seen before.

Now, Rockefeller University scientists F. Nina Papavasiliou and Michel C. Nussenzweig have independently identified a tiny molecule that directly binds to and curbs the production of this potent gene mutator, an enzyme called AID. By tightly controlling levels of AID, this molecule, known as microRNA-155, stands between two opposing bastions of health: an immune system that can ward off an ever-growing legion of infectious microbes and one that can send the body down the road to some of the most aggressive and lethal forms of cancer 鈥� leukemia and B cell lymphomas.

The findings of both papers, reported back-to-back in the May 16 issue of Immunity, define a new role for miR-155. In the past, it has been implicated in the onset and development of cancer. Now, this research suggests that when it specifically binds to AID, it can potentially thwart it. 鈥淲e used a different approach and different tools, yet we said the same things and reached the same conclusions,鈥� says Papavasiliou, head of the Laboratory of Lymphocyte Biology. 鈥淚t鈥檚 pretty powerful stuff.鈥�

In B lymphocytes, AID specifically targets a small strip of DNA that encodes an antibody molecule. When AID mutates this DNA segment even slightly the altered gene can either give rise to an antibody that binds to a different invader or one that clings tighter to its original target, maximizing the chance that it will be effective. By regulating how much AID is present in these cells, miR-155 helps ensure that there is just enough AID to only mutate this strip of DNA.

But there鈥檚 a catch, explains Grace Teng, a graduate student in the Papavasiliou lab. She found that while too little AID impairs the immune system鈥檚 ability to fight infections, too much AID produces neither a more diverse nor a more effective repertoire of antibodies to keep invaders at bay. Instead, excess levels of the enzyme cause pieces of the antibody genes to swap places with other genes on different chromosomes. This process, called translocation, doesn鈥檛 always lead to cancer, but it is a hallmark of the disease.

鈥淪o what鈥檚 clear from this work is that when you overexpress AID, it doesn鈥檛 generate more mutations to make better antibodies,鈥� says Papavasiliou. 鈥淚t is shunted into a translocation pathway.鈥�

When graduate student Yair Dorsett and postdoc Kevin McBride, both members of the Nussenzweig lab, either looked at mice in which miR-155 couldn鈥檛 attach to AID (the team altered AID鈥檚 binding site) or mice that couldn鈥檛 produce miR-155 at all, they, like the Papavasiliou team, didn鈥檛 find a notable rise in mutations. Rather, they found up to a fifteen percent increase in a translocation pathway whereby the oncogene c-myc breaks off from its designated spot and migrates to the strip of antibody-encoding DNA. The vigorous gene activity that occurs in this region can ramp up the oncogene鈥檚 expression and lead to a highly aggressive cancer known as Burkitt鈥檚 lymphoma.

Although other lymphomas have been found to overexpress miR-155, Burkitt鈥檚 lymphoma lacks the expression of it. Without miR-155, high, unregulated levels of AID could generate the translocations that can send a B lymphocyte down the road to cancer. 鈥淐ells from different kinds of lymphomas all have their distinct signatures,鈥� says Dorsett. 鈥淪o understanding miR-155鈥檚 role in the genesis of these diseases may help us understand the differences between them.鈥�

Citations: Cell Immunity 28(5): 621-629 (May 16, 2008)
Cell Immunity 28(5): 630鈥�638 (May 16, 2008)

Source: Rockefeller University