Researchers have learned more about an enzyme that is key to helping cells repair DNA after it sustains damage. DNA has to be maintained for the health of an organism, and cells have molecules to fix genetic material that suffers damage from reactive oxygen species and other deleterious natural chemicals. DNA maintenance and repair is still not well understood, but scientists have reported new details about one enzyme that acts to respond to DNA damage and work to repair it, called APE2. One part of that enzyme, the Zf-GRF domain, has been shown to carry out an important function - allowing enzymes to line up properly so they can bind to DNA.
"We study APE2, which plays an important role in repairing DNA following oxidative stress," said one study leader, Shan Yan of the Department of Biological Sciences at the University of North Carolina at Charlotte (UNCC). "We are trying to understand the structure and function of this enzyme because it's not very well characterized, but plays a central role in the cellular response to oxidative DNA damage."
Yan’s team worked in collaboration with the research team of R. Scott Williams at the Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS) in the National Institutes of Health. Their findings were reported in the Proceedings of the National Academy of Sciences.
"APE2 has different domains and one of the least understood is called Zf-GRF, which we have succeeded in characterizing," said Yan. "We found that its function is to interact specifically with a single strand of DNA. If this domain does not bind to the single strand of DNA, APE2 doesn't promote its catalytic activity and it cannot move forward in the appropriate 3' to 5' direction along the strand. "
Yan noted that the Zf-GRF domain is present in several other proteins as well. It presents a "claw-like" structure, with other components encircling a zinc molecule. There is a high degree of similarity in the molecule regardless of the organism carrying it, so it’s said to be highly conserved through evolution.
"Though it's a very small domain - about 50 amino acids - it's highly conserved in evolution. This enzyme domain is the same across many species, which implies that it's important. It is also found not only in APE2, but also in many other enzymes, including important DNA metabolism enzymes such as Topoisomerase 3α and NEIL3. Our finding can be applied to future studies on those proteins."
Williams explained that Zf-GRF has a uniform structure because this molecular tool has a critical and useful function in the regulation of enzymatic activity. "The APE2 DNA processing activity is necessary for activation of "cellular checkpoints", an alarm which is signaled when DNA damage is detected, and helps to prevent further damage from occurring, while making it possible for a cell to fix these toxic lesions. If left in an unrepaired and un-signaled state, such oxidative DNA damage can be a major contributing factor to cancer progression, amongst other maladies."