AID was found to cause damage in different parts of the genome and not just antibody genes, notes study in Cell.

Rockefeller University scientists have discovered that the same enzyme that enables immune cells to continuously evolve new defenses is also responsible for the genetic malfunction that causes Burkitt’s lymphoma.

The activation-induced deaminase (AID) enzyme, previously thought to cause DNA breaks only in antibody genes, is probably involved in a broader range of cancers as well, according to the team.

“We strongly suspect that many or all of the translocations of human lymphomas in mature B cells are the product of this enzyme,” says Michel C. Nussenzweig, M.D., Ph.D., head of the laboratory of molecular immunology at Rockefeller University. “And there’s more and more data to show that it may be involved in other cancers as well. It’s been identified in stomach cancers, for instance.”

A very specific translocation causes Burkitt’s lymphoma. It involves a DNA break in an immune system antibody gene and the much more rare break in a cancer-promoting gene called c-myc. Previous work had shown that AID was responsible for breaking antibody genes but not c-myc.

To prove that AID was indeed the culprit behind the c-myc break, the investigators started by deleting the promoter region of the c-myc oncogene in a mutant line of mice, rendering the gene inactive. By looking for and not finding the specific translocation in these mice, the researchers showed that c-myc had to be active for its DNA break to take place.

The team then inserted a DNA tag into the mouse genome that induced a break at the c-myc gene, which occurs only very rarely if left to its own devices. They found that the artificially created breaks were comparable in almost every way to the breaks caused by AID. When they looked for the translocation in mice that didn’t produce this enzyme, however, they were nowhere to be found.

The scientists caution that because AID normally enables the genetic experimentation that’s critical to an effective immune response, shutting it down even to fight cancer is perilous. A pharmaceutical AID inhibitor could still prove useful in treating certain tumors that are expressions of this gene mutator, they add.

The findings are published in the December 12 edition of Cell.

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