Not too "picky" enzyme
How the environment contributes to the development of diseases
NanoNewsNet based on the materials of the National Institutes of Health:
NIH Scientists Determine How Environment Contributes to Several Human DiseasesUsing a new imaging method, scientists have found that the biological machinery responsible for assembling DNA can embed nucleotides damaged as a result of environmental exposure into its chain.
Such damaged molecules are triggers of cell death underlying several human diseases. A new study provides a possible explanation for how one type of DNA damage leads to the development of cancer, diabetes, hypertension, cardiovascular and pulmonary diseases and Alzheimer's disease.
Using a new imaging method, scientists from the National Institutes of Health (NIH) have found that the molecular machinery responsible for assembling DNA can embed molecules damaged as a result of environmental exposure into its chain. Such damaged molecules are triggers of cell death underlying several human diseases. An article published online in the journal Nature (Freudenthal et al., Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide) provides a possible explanation for how one type of DNA damage leads to the development of cancer, diabetes, hypertension, cardiovascular and pulmonary diseases and Alzheimer's disease.
To determine that DNA polymerase, the enzyme responsible for the assembly of nucleotides, or DNA building blocks, embeds nucleotides with a specific type of damage into the DNA chain, the researchers used time-lapse crystallography. Frame–by-frame crystallography is a method for obtaining snapshots of biochemical reactions occurring in cells.
The head of the study, Samuel Wilson, MD, explained that the type of damage studied by him and his colleagues is caused by oxidative stress, or the active action of free oxygen molecules formed in response to environmental factors, such as ultraviolet radiation, nutritional characteristics, chemical compounds in paints, plastics and other consumer goods. According to him, scientists had previously assumed that DNA polymerase could embed nucleotides damaged by an additional oxygen atom into DNA.
"If one of these oxidized nucleotides is embedded in the DNA chain, it cannot form a pair with the opposite nucleotide, as it usually happens, which leads to the formation of a gap in the DNA," explains Dr. Wilson. "Before our article, no one had seen exactly how polymerase does this, and did not understand what the possible consequences were."
The damaged nucleotide embedded in DNA by the enzyme DNA polymerase (large gray molecule in the figure) is not able to form a pair with an intact nucleotide of another chain, as it normally happens. As a result, the oxidized nucleotide prevents DNA repair or causes both chains to break. These molecular events can eventually lead to the development of many diseases. (Fig. Bret Freudenthal, NIEHS)Dr. Wilson and his colleagues saw this process in real time by creating crystal complexes from DNA, polymerase, and oxidized nucleotides.
The method not only showed the stages of embedding the damaged nucleotide, but also that the newly formed defective DNA blocks the elimination of the gap by its repair mechanisms. The gap formed in the DNA prevents further DNA repair and replication or leads to the immediate rupture of both chains.
A large number of such double-stranded breaks are fatal to the cell and are the starting point for the development of diseases. However, from the point of view of the scientist, the same phenomenon gives some hope to oncologists, as it allows them to destroy cancer cells.
"One of the characteristic features of cancer cells is their predisposition to more pronounced oxidative stress than normal cells," comments Bret Freudenthal, PhD, lead author of the article. "Cancer cells counter this by using an enzyme that removes oxidized nucleotides that would otherwise be embedded in the genome by DNA polymerase. In studies conducted by other groups, it was found that the suppression of this enzyme can achieve the predominant destruction of cancer cells."
Wilson and Freudenthal emphasize that the number of oxidized nucleotides in the total pool of nucleotides is usually under strict control, but if they accumulate and begin to outnumber intact molecules quantitatively, DNA polymerase adds more and more defective molecules to the chain. Oxidation-suppressing molecules, known as antioxidants, reduce the level of oxidized nucleotides and may help prevent some of the diseases.
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