MIT researchers have revealed how a cellular DNA repair system responds to exposure to NDMA, a probable carcinogen. The team found that too little activity of one enzyme necessary for DNA repair leads to much higher cancer rates, while too much activity can produce tissue damage. Their study was published in Cell Reports.
Activity levels of this enzyme, called AAG, can vary greatly among different people, and measuring those levels could allow doctors to predict how people might respond to NMDA exposure, says Bevin Engelward, senior author. "It may be that people who are low in this enzyme are more prone to cancer from environmental exposures," she says.
In the new study, the team studied mice with high levels of AAG—six times the normal amount—and mice with AAG knocked out. After exposure to the chemical NDMA, the mice with no AAG had many more mutations and higher rates of cancer in the liver, where NDMA has its greatest effect. Mice with sixfold levels of AAG had fewer mutations and lower cancer rates, at first glance appearing to be beneficial. However, in those mice, the researchers found a great deal of tissue damage and cell death in the liver. Mice with normal amounts of AAG showed some mutations after NDMA exposure but overall were much better protected against both cancer and liver damage.
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"Nature did a really good job establishing the optimal levels of AAG, at least for our animal model," Engelward added. "What is striking is that the levels of one gene out of 23,000 dictates disease outcome, yielding opposite effects depending on low or high expression." If too low, there are too many mutations; if too high, there is too much cell death. The researchers next plan to study the effects of chronic, low-level exposure to NDMA in mice, which they hope will shed light on how such exposures might affect humans. "That's one of the top priorities for us, to figure out what happens in a real world, everyday exposure scenario," lead author Jennifer Kay says.