This year's Nobel Prize in chemistry was given to three scientists who each focused on one piece of the DNA repair puzzle. Now a new study, reported online Oct. 28 in the journal Nature, reports the discovery of a new class of DNA repair enzyme.
When the structure of DNA was first discovered, scientists imagined it to be extremely chemically stable, which allowed it to act as a blueprint for passing the basic traits of parents along to their offspring.
The new type of DNA repair enzyme, AlkD on the left, can identify and remove a damaged DNA base without forcing it to physically "flip" to the outside of the DNA backbone, which is how all the other DNA repair enzymes in its family work, as illustrated by the human AAG enzyme on the right. The enzymes are shown in grey, the DNA backbone is orange, normal DNA base pairs are yellow, the damaged base is blue and its pair base is green.
Credit: Brandt Eichman, Vanderbilt University
Although this view has remained prevalent among the public, biologists have since learned that the double helix is in fact a highly reactive molecule that is constantly being damaged and that cells must make unceasing repair efforts to protect the genetic information that it contains.
"It's a double-edged sword," said Brandt Eichman, associate professor of biological sciences and biochemistry at Vanderbilt University, who headed the research team that made the new discovery. "If DNA were too reactive then it wouldn't be capable of storing genetic information. But, if it were too stable, then it wouldn't allow organisms to evolve."
The DNA double-helix has a spiral staircase structure with the outer edges made from sugar and phosphate molecules joined by stair steps composed of pairs of four nucleotide bases (adenine, cytosine, guanine and thymine) that serve as the basic letters in the genetic code.
There are two basic sources of DNA damage or lesions: environmental sources including ultraviolet light, toxic chemicals and ionizing radiation and internal sources, including a number of the cell's own metabolites (the chemicals it produces during normal metabolism), reactive oxygen species and even water.
"More than 10,000 DNA damage events occur each day in every cell in the human body that must be repaired for DNA to function properly," said first author Elwood Mullins, a postdoctoral research associate in the Eichman lab.
The newly discovered DNA repair enzyme is a DNA glycosylase, a family of enzymes discovered by Tomas Lindahl, who received this year's Nobel prize for recognizing that these enzymes removed damaged DNA bases through a process called base-excision repair. It was the first of about 10 different DNA repair pathways that biologists have identified to date.
In base-excision repair, a specific glycosylase molecule binds to DNA at the location of a lesion and bends the double-helix in a way that causes the damaged base to flip from the inside of the helix to the outside. The enzyme fits around the flipped out base and holds it in a position that exposes its link to the DNA's sugar backbone, allowing the enzyme to detach it. After the damaged base has been removed, additional DNA-repair proteins move in to replace it with a pristine base.
Eichman and his collaborators discovered that a glycosylase called AlkD found in Bacillus cereus - a soil-dwelling bacterium responsible for a type of food poisoning called the "fried rice syndrome" - works in a totally different fashion. It does not require base flipping to recognize damaged DNA or repair it.
Seven years ago, Eichman's group discovered that AlkD had a structure unlike any of the other glycosylases. The researchers determined that the enzyme was able to locate damaged DNA that has a positive electrical charge. This is the signature of alkylation, attaching chains of carbon and hydrogen atoms of varying lengths (methyl, ethyl etc.), to specific positions on the damaged base. Positively charged alkylated bases are among the most abundant and detrimental forms of DNA damage. However, they are highly unstable, which has made them very difficult to study.
Now the researchers have captured crystallographic snapshots of AlkD in the act of excising alkylation damage and have shown that the enzyme doesn't use base flipping. Instead, they have determined that AlkD forms a series of interactions with the DNA backbone at and around the lesion while the lesion is still stacked in the double helix. Several of these interactions are contributed by three amino acids in the enzyme that catalyze excision of the damaged base.
According to the researchers, the AlkD mechanism has some remarkable properties:
"Our discovery shows that we still have a lot to learn about DNA repair, and that there may be alternative repair pathways yet to be discovered. It certainly shows us that a much broader range of DNA damage can be removed in ways that we didn't think were possible," said Eichman. "Bacteria are using this to their advantage to protect themselves against the antibacterial agents they produce. Humans may even have DNA-repair enzymes that operate in a similar fashion to remove complex types of DNA damage. This could have clinical relevance because these enzymes, if they exist, could be reducing the effectiveness of drugs designed to kill cancer cells by shutting down their ability to replicate."
Co-authors of the paper are graduate student Rongxin Shi and Postdoctoral Research Associate Zack Parsons from the Eichman Lab, Professor Sheila David and graduate student Philip Yuen from University of California, Davis and Professor Yasuhiro Igarashi from Toyama Prefectural University.
The research was supported by National Science Foundation grants MCB-1122098 and MCB-1517695 and National Institutes of Health grants R01ES01625 and R01CA067985.
David F Salisbury | EurekAlert!
Study shines light on brain cells that coordinate movement
26.06.2017 | University of Washington Health Sciences/UW Medicine
New insight into a central biological dogma on ion transport
26.06.2017 | Aarhus University
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
26.06.2017 | Life Sciences
26.06.2017 | Physics and Astronomy
26.06.2017 | Information Technology