NIH: oxidation causes human disease through DNA polymerase

Using a new imaging technique, researchers at the Institute of health found that the molecular mechanism for building DNA can insert molecules into DNA chains, which have been damaged by exposure to the environment The damage of these molecules can trigger cell death, leading to some human diseases The work, published online in science, provides a theory that can be used to explain why DNA damage causes cancer, diabetes, high blood pressure, cardiovascular and lung diseases, and Alzheimer's disease Researchers at the Institute of Environmental Health Sciences (NIEHS) used timed crystallization to determine when DNA polymerase, an enzyme responsible for assembling DNA nucleotides, binds specific nucleotides to damaged DNA strands Time lapse crystals are a technique that can be used to generate images when biochemical reactions take place in cells Dr Samuel Wilson, senior researcher of NIEHS in the team, explained that the damage caused by oxidative stress or free oxygen molecules corresponds to the corresponding environment, such as ultraviolet radiation, diet, and oxide in paints, plastics and other consumer goods He said scientists suspect that DNA polymerases disrupt inserted nucleotide molecules by carrying nucleotides with extra oxygen atoms "When these oxidized nucleotides replace the nucleotides in the DNA strand, they don't pair with the opposite nucleotides normally, which creates gaps in the DNA," Wilson said "Before this article, no one really saw how polymerases do this, or how they affect downstream." Wilson and his colleagues saw this process in real time through a crystal complex of DNA, polymerases and oxidized nucleotides, and captured these crystals at different points in time by the method of time-lapse crystals This method not only reveals the stage of nucleotide insertion, but also indicates a new mechanism of DNA stop and DNA repair Cracks in DNA can further prevent DNA repair and replication, and can also cause double strand breaks "The damaged nucleotide sites are similar to the train tracks where the boards are missing," Wilson said "When the engine is running, the train will jump on the track, causing the cars on the train to collide with each other." A large number of chain impacts and double chain breaks are lethal to cells, and this will be called the jumping point of disease development However, this is good news for researchers trying to destroy cancer cells "A characteristic of cancer cells is that they tend to have more oxidative stress than normal cells," said BRET Freudenthal, Ph.D., a postdoctoral fellow at Wilson's group and the lead researcher of the paper "Cancer cells solve this problem by using an enzyme that removes oxidized nucleotides, otherwise they are inserted into the genome by DNA polymerases Other groups of researchers do research, if we inhibit this enzyme, we can give priority to killing cancer cells " Wilson and Freudenthal stressed that the amount of oxidized nucleotides in the pool is usually strictly controlled, but if they accumulate and start to outnumber intact nucleotides, DNA polymerases will add them more to the DNA strand Known antioxidants, molecules that inhibit oxidation, etc., can reduce the level of oxidized nucleotides, which can help people prevent certain diseases.