Disabling DNA repair might be crucial to halting cancer

By Amanda Siegfried / August 2010

When DNA inside a cell is damaged by radiation, the damage needs to be repaired quickly if the cell is to survive. Disabling such repair mechanisms in cancer cells, but not in healthy tissue, could hold the ticket to killing cancer selectively while limiting damage to normal cells.

In a new study published in Molecular and Cellular Biology, lead author Dr. Tej Pandita, professor of radiation oncology, and his colleagues found that reining in an enzyme known to play a role in DNA repair might boost cancer’s sensitivity to radiation.

The study focused on the enzyme MOF, which interacts with a molecule called a histone. Histones form a type of spool structure around which DNA is twisted. Specifically, MOF adds a chemical called an acetyl group to the histone dubbed H4K16. This acetylation process causes the histone molecule to change shape, a critical step in allowing DNA repair enzymes access to the damaged area.

Dr. Pandita’s team found that by depleting MOF levels in cancer cells, they ultimately could reduce this DNA repair activity. The results suggest a one-two punch to increasing the effectiveness of radiation therapy, he said: Treat cancer cells with DNA-damage-inducing radiation, and inhibit MOF selectively in those cells.

“We have shown that if we can deplete MOF in tumor cells, but not in healthy cells, we could gain a therapeutic advantage,” said Dr. Pandita, who also is a member of the Harold C. Simmons Comprehensive Cancer Center. “By affecting MOF in tumor cells, they will be weakened and unable to recover after radiation exposure.”

The next step in the research will be to characterize further the MOF-histone interaction and its role in activating DNA double-strand break repair, Dr. Pandita said.

Other UT Southwestern researchers involved in the study were Dr. Rakesh Kumar, postdoctoral researcher in radiation oncology; Dr. Sairie So, postdoctoral researcher in radiation oncology; Dr. Matthew Porteus, assistant professor of pediatrics and biochemistry; and Dr. David Chen, professor of radiation oncology. The National Institutes of Health funded the research.