A Protein to Tie Up Loose Ends

Release Date:
4/2/2003
Contact:
NIGMS OCPL
301-496-7301
info@nigms.nih.gov

Our genetic material is under constant assault, bombarded by a variety of sources that break the long strands of DNA in our chromosomes. The culprits? Cosmic radiation and highly reactive molecules, called free radicals, found in sources ranging from smog to nitrite food preservatives. Breaks in DNA can cripple cells' ability to make the proteins they need to survive and--if passed on to subsequent generations of cells--can lead to a host of diseases, including cancer. Cells have repair mechanisms that rejoin broken DNA strands, but sometimes the genetic coding for these repair mechanisms is defective. When this happens, cells cannot manufacture the repair proteins they need.

A very serious immune system disorder, severe combined immunodeficiency disease, affects people who inherit a particular type of genetic defect in their cellular repair mechanisms. This disease was featured in the 1976 television movie, The Boy in the Plastic Bubble. Researchers located the gene responsible for about 15 percent of severe combined immunodeficiency cases and named it Artemis, after the Greek goddess for the protection of children. But the protein product of the Artemis gene was unknown.

Dr. Michael Lieber of the University of Southern California's Keck School of Medicine has now identified the Artemis protein and described how it works. He discovered that it is an enzyme essential for repairing breaks in DNA by trimming away the frayed tails left at randomly broken DNA ends. Other proteins then rejoin the DNA segments. This housekeeping activity is crucial for survival in all cells, and those lacking the Artemis protein quickly accumulate fragmented chromosomes as more and more of the DNA strands within the chromosomes break. Dr. Lieber also discovered that Artemis has an additional function within specialized immune system cells called lymphocytes. These cells use Artemis to shuffle the DNA that makes up immunity genes in order to generate the wide range of antibodies and other molecules needed to combat many different bacteria, viruses, fungi, and other threats. Without the Artemis protein, these immune system molecules fail to develop, leaving the body vulnerable to any number of diseases and infections.

A drug that temporarily inhibits the activity of Artemis could boost the effectiveness of radiation therapy for cancer by blocking the ability of cancer cells to repair themselves after radiation damage. With this goal in mind, Dr. Lieber plans to screen for drugs that inhibit the Artemis protein. Beyond this potential application of Dr. Lieber's research, the new knowledge he has provided about Artemis adds to our general understanding of DNA repair mechanisms, a process vital to the survival of our cells.