NEW BRUNSWICK/PISCATAWAY, N.J. – “Change is inevitable,” as the saying goes, particularly in hereditary DNA – the long chains of precisely ordered bases that make up the genome. These changes, or mutations, occur naturally, but they can also be caused by radiation, toxic substances, chemotherapy or even sunlight. When the DNA changes, so do the genetic messages it carries.
At Rutgers, The State University of New Jersey, doctoral candidate Seema Sharma and Assistant Professor Jeehiun Katherine Lee, both from the department of chemistry and chemical biology, have taken some of the mystery out of how the human body copes with mutations. They found that when some of the DNA bases become mutated, they increase in acidity. This, they discovered, could be a signal for the repair crews to come in. Enzymes, proteins that induce chemical reactions, actually do the repair work.
Sharma and Lee used a novel approach to their research, an innovation that clearly made their discoveries possible. “To make the environment more unbiased, we did our experiments in a vacuum chamber, not in a liquid solution as is typically used,” said Lee. She explained that much of what happens in the body’s cells does not take place in a solution. “The gaseous conditions in the vacuum chamber give us the most neutral environment, and from there we can infer what might happen under other conditions.”
Initial findings from their studies were described in a paper (ORGN 283) by the two investigators presented at the 224th national meeting of the American Chemical Society in Boston.
Their research into the mechanisms the human body uses to deal with mutations looked at the microscopic properties and behavior of DNA bases and mutated bases, and at the enzymes that target these bases for repair. “There are naturally occurring enzymes in the body that work to preserve the genome,” said Lee. “They first identify and then remove a mutated section of DNA. We found some answers to why this may happen, and now we hope to find out about the ‘how.’”
Mutations happen all the time, and they are really the building blocks of evolution. They increase the variability in a species to which natural selection can then give emphasis. Mutations, however, tend to be disruptive. They can throw the body out of kilter, changing its regular operational routines.
“We wanted to understand what kinds of changes took place in the mutated DNA bases that enabled the enzymes to pinpoint them. Why are the mutated bases being singled out?” asked Lee.
Sharma and Lee focused on alkylated adenines, a class of DNA bases that are mutated through a specific change in molecular structure. The more reactive a particular base is, the more easily it might be found and removed by an enzyme. In this case, how reactive a base is depends upon how acidic it is. The investigators began to explore the relationship between the acidity of the mutated bases and their ease of removal.
They discovered that 3-methyladenine, the most common mutation in this group, should be particularly prone to removal because of its unusually high acidity. The acidity of other mutated DNA bases was also measured to see how the acidity relates back to the enzyme activity.
The next step for the researchers will be to investigate the actual mechanisms the enzymes use to identify bases that have been mutated. Some of these enzymes are highly specific, focusing on only one kind of alkylated base, while other enzymes are not so picky. “Some enzymes will just take care of lots of different kinds of bases, and scientists don’t understand why some are so specific and some are not,” said Lee. “We are working toward an understanding of these mechanisms, as well.”
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