The protein, HMGB1, was previously hypothesized to block DNA repair, senior author Karen Vasquez, Ph.D., associate professor in M. D. Anderson's Department of Carcinogenesis at the Science Park - Research Division in Smithville, Texas.
Identification and repair of DNA damage is the frontline defense against the birth and reproduction of mutant cells that cause cancer and other illnesses.
Pinpointing HMGB1's role in repair raises a fundamental question about drugs under development to block the protein, Vasquez said. The protein also plays a role in inflammation, so it's being targeted in drugs under development for rheumatoid arthritis and sepsis.
"Arthritis therapy involves long-term treatment," Vasquez said. "Our findings suggest that depleting this protein may leave patients more vulnerable to developing cancer."
Long known to attach to sites of damaged DNA, the protein was suspected of preventing repair. "That did not make sense to us, because HMGB1 is a chromosomal protein that's so abundant that it would be hard to imagine cell repair happening at all if that were the case," Vasquez said.
In a series of experiments reported in the paper, Vasquez and first author Sabine Lange, a doctoral candidate in the Graduate School of Biomedical Sciences, tracked the protein's impact on all three steps of DNA restoration: access to damage, repair and repackaging of the original structure, a combination of DNA and histone proteins called chromatin.
First, they knocked out the gene mouse embryonic cells and then exposed cells to two types of DNA-damaging agents. One was UV light, the other a chemotherapy called psoralen that's activated by exposure to darker, low frequency light known as UVA. In both cases, the cells survived at a steeply lower rate after DNA damage than did normal cells.