Scientists identify a key regulator of DNA mutations

Jun 10, 2008

As a general rule, your DNA is not something you want rearranged. But there are exceptions – 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 — 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. “We used a different approach and different tools, yet we said the same things and reached the same conclusions,” says Papavasiliou, head of the Laboratory of Lymphocyte Biology. “It’s pretty powerful stuff.”

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’s a catch, explains Grace Teng, a graduate student in the Papavasiliou lab. She found that while too little AID impairs the immune system’s 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’t always lead to cancer, but it is a hallmark of the disease.

“So what’s clear from this work is that when you overexpress AID, it doesn’t generate more mutations to make better antibodies,” says Papavasiliou. “It is shunted into a translocation pathway.”

When graduate student Yair Dorsett and postdoc Kevin McBride, both members of the Nussenzweig lab, either looked at mice in which miR-155 couldn’t attach to AID (the team altered AID’s binding site) or mice that couldn’t produce miR-155 at all, they, like the Papavasiliou team, didn’t 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’s expression and lead to a highly aggressive cancer known as Burkitt’s lymphoma.

Although other lymphomas have been found to overexpress miR-155, Burkitt’s 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. “Cells from different kinds of lymphomas all have their distinct signatures,” says Dorsett. “So understanding miR-155’s role in the genesis of these diseases may help us understand the differences between them.”

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

Source: Rockefeller University

Explore further: Manatees could lose their endangered species status

add to favorites email to friend print save as pdf

Related Stories

Is anyone immune to the social media echo chamber?

27 minutes ago

It's becoming increasingly obvious that as we spend more time communicating via social media, we are disappearing into bubbles. We receive information from the same sources and witness the views of the same ...

Cuckoos hide from each other using 'cryptic' eggs

37 minutes ago

Cuckoos aren't the kind of parents you'd want. They never raise their young ones, leaving that job to other birds. They achieve this by laying their eggs in other expectant birds' nests, who treat them as ...

Recommended for you

Researchers discover new strategy germs use to invade cells

53 minutes ago

The hospital germ Pseudomonas aeruginosa wraps itself into the membrane of human cells: A team led by Dr. Thorsten Eierhoff and Junior Professor Dr. Winfried Römer from the Institute of Biology II, members of the Cluster ...

Progress in the fight against harmful fungi

1 hour ago

A group of researchers at the Max F. Perutz Laboratories has created one of the three world's largest gene libraries for the Candida glabrata yeast, which is harmful to humans. Molecular analysis of the Candida ...

Genetically tracking farmed fish escaping into the wild

1 hour ago

European sea product consumption is on the rise. With overfishing being a threat to the natural balance of the ocean, the alternative is to turn to aquaculture, the industrial production of fish and seafood. ...

User comments : 0