Researchers at Vanderbilt University, Pennsylvania State University and the University of Pittsburgh have discovered a new mechanism that detects and repairs a more common form of DNA damage called alkylation.
In a typical day, about one million bases in the DNA of a human cell are damaged. These lesions are caused by a combination of normal chemical activity within the cell and exposure to radiation and toxins coming from environmental sources including cigarette smoke, grilled foods, UV rays and industrial waste. These lesions cause structural damage to the DNA molecule, and can dramatically alter the cell’s way of reading the information encoded in its genes. Luckily, repairing damage and maintaining the integrity of its DNA is one of the cell’s highest priorities.
As cells age however, the DNA repair process can no longer keep up with ongoing DNA damage. The cell then suffers one of three possible outcomes:
* An irreversible state of dormancy, known as senescence (http://en.wikipedia.org/wiki/Senescence)
* Cell suicide, also known as apoptosis (http://en.wikipedia.org/wiki/Apoptosis) or programmed cell death
When cells become senescent, alterations in their gene regulation cause them to function less efficiently, which inevitably causes disease. The DNA repair ability of a cell is vital to its normal functioning and to the health and longevity of the organism. Many genes that are shown to influence lifespan are associated with DNA damage repair and protection.
“There is a general belief that DNA is ‘rock solid’ – extremely stable,” said Brandt Eichman (http://structbio.vanderbilt.edu/faculty/eichman.php), associate professor of biological sciences at Vanderbilt, who directed the project. “Actually DNA is highly reactive,” he was quoted as saying.
According to the Vanderbilt study, when a DNA base becomes alkylated, it forms a lesion that distorts the shape of the molecule enough to prevent successful replication. Human cells contain a single glycosylase (http://en.wikipedia.org/wiki/DNA_glycosylase), named AAG that repairs alkylated bases. It’s specialized to detect and delete “ethenoadenine” bases, which have been deformed by combining with highly reactive, oxidized lipids in the body.
“It’s hard to figure out how glycosylases recognize different types of alkylation damage from studying AAG since it recognizes so many. So we have been studying bacterial glycosylases to get additional insights into the detection and repair process,” said Eichman.
That is how they discovered the bacterial glycosylase AlkD with its unique detection and deletion scheme. “All the known glycosylases work in basically the same fashion: hey flip out the deformed base and hold it in a special pocket while they excise it. AlkD, by contrast, forces both the deformed base and the base it is paired with to flip to the outside of the double helix.”
“Understanding protein-DNA interactions at the atomic level is important because it provides a clear starting point for designing drugs that enhance or disrupt these interactions in very specific ways,” says Eichman. “So it could lead to improved treatments for a variety of diseases, including cancer.”
So there is a vast body of evidence that correlates DNA damage to death and disease. As indicated by the findings of the Vanderbilt study, increasing the activity of some DNA repair enzymes could cause a decrease in the rate of cell damage which would result in adding many healthy and disease-free years to our aging population.
Read about the DNA Repair study: (http://news.vanderbilt.edu/2010/10/newly-discovered-dna-repair-mechanism/)
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