Immune Deficiency Due to Defective DNA Repair

A mutation in a gene whose product is responsible for repair of damaged DNA molecules is the underlying cause of a form of severe immunodeficiency. This finding is reported in a study published in the March 22, 2002, issue of Cell.

The gene was first described in April of 2001 by a team of French researchers who named it and its product Artemis (after the Greek goddess for the protection of children). However, they did not report what kind of protein it was nor what its function might be.

Now, Dr. Michael Lieber from the Keck School of Medicine at the University of Southern California (Los Angeles CA, USA) and his colleagues from the University of Ulm (Germany; www.uni-ulm.de) have conclusively demonstrated that Artemis is a key protein in the repair of damage to double-stranded DNA, a process called NHEJ (nonhomologous DNA end joining). In the NHEJ pathway, the ends of the broken DNA strands are trimmed and rejoined to one another. "What Artemis does is trim away the damaged parts of the DNA so that the strands can be joined,” said Lieber.

Artemis and the NHEJ pathway are so essential that mice lacking NHEJ usually die at birth. Those that survive generally lack an immune system entirely and experience accelerated aging. Humans with a defective Artemis protein suffer from practically nonfunctional immune systems. "That is because the immune system creates its defenses by cutting and then rejoining bits of nuclear DNA (the rejoining relies on NHEJ),” says Lieber. "Without Artemis, the cells cannot create the antibodies necessary to go after the myriad pathogenic invaders we regularly encounter.”

For normal cells, Artemis and the NHEJ pathway are absolutely critical for survival. Lieber explains this is because of the extreme vulnerability of our cells to DNA damage. "Indeed,” he said, "all you have to do is take some cells out of the organism in which they live and look at them under a microscope, and you will find that 5-10% of them will have at least one broken chromosome.”




Related Links:
USC, Keck School of Medicine
University of Ulm