Manipulating DNA Repair Crews to Combat Cancer

Researchers from Johns Hopkins University report on a cascade of events that appears to correlate with early cancer recurrence and decreased overall survival.

A new study is suggesting that some cancers may develop because a normal part of a cell’s machinery generally used to repair DNA damage is diverted from its usual task. Researchers from Johns Hopkins University report in the May 8 issue of Cancer Cell on a cascade of events that appears to correlate with early cancer recurrence and decreased overall survival. The authors write that this new discovery could lead to the identification of novel molecular targets for anticancer drugs or tests for cancer recurrence.

The scientists uncovered a link with a DNA-binding protein (CHD4) associated with DNA damage repair. The team exposed human colon cancer cells in the laboratory to hydrogen peroxide, which damages DNA through an inflammatory-like process. The experiments showed that CHD4 was present at the DNA damage sites within minutes of exposure to hydrogen peroxide, and was soon accompanied by a repair crew of other proteins, composed in part of DNA methyltransferases.

The researchers used a laser beam to cause DNA damage in the colon cancer cell lines and found CHD4 and its crew of repair proteins swooped into the damage site. When the team stopped cells from making CHD4 by genetically disrupting the gene, the accompanying proteins were no-shows after exposure to hydrogen peroxide or the laser.

“The presence of CHD4 and its accompanying proteins may be part of a universal system for repairing DNA damage,” said Stephen B. Baylin, MD, who is a professor of Oncology and Medicine and associate director for research programs at the Kimmel Cancer Center at Johns Hopkins in Baltimore. “Our experiments suggest that CHD4 and the resulting methylation is a really important phenomenon associated with the cause of colon and probably many other cancer types.”

Baylin and his colleagues found that eight genes most likely to be already methylated and thus turned off in colon cancer cells may be potential tumor suppressors. Further investigation showed these genes were also already enriched with CHD4. When researchers prevented cells from making CHD4, these genes lost their methylation and became reactivated, able to produce proteins that prevented the spread of cancer cells.

Checking The Cancer Genome Atlas, investigators found that a significant subset of colon, lung, and other cancers (between 30% and 40%) had much higher levels of CHD4 than healthy tissues. In addition, they found that CHD4 interacts directly with an enzyme called 8-oxoguanine glycosylase (OGG1) when it becomes damaged. When the researchers removed this enzyme from cells, CHD4 failed to arrive at sections of damaged DNA.

When the researchers color-stained the DNA of colon cancer cells to find the most likely locations of OGG1, they found it at the locations of the eight tumor suppressor genes that are often turned off when cancer occurs. The researchers theorize that finding ways to reduce the amount of CHD4 in tumors could be a new way of attacking cancer. They also proposed that it may be possible to gauge the risk of cancer recurrence by tracking high levels of OGG1.