Humans need energy to function, so might be hard to imagine how a naturally occurring process that generates power for the body can also harm its cells. But it does, according to Samuel Wilson, M.D., and members of his NIEHS DNA Repair and Nucleic Acid Enzymology Group.
Based on work done by Wilson’s research fellow Melike Caglayan, Ph.D., the team determined how this particular type of damage leads to DNA strand breaks, and ultimately, cell death. The scientists used biochemical and cell biology methods, along with X-ray crystallography, to uncover the inner workings of cells. Their recent findings, published in the journal Nature Communications, may help scientists better understand the origins of some human diseases.
Wilson said that cellular mitochondria, which are specialized energy-producing machines that fuel cells, also produce molecules that harm cellular DNA and proteins. These harmful molecules, known as reactive oxygen species (ROS), can alter the chemical composition of the compounds used to build DNA, as well as DNA itself. If the DNA building blocks are not restored to their original shape, or if DNA is structurally modified due to ROS, the DNA can break, triggering the cell to self-destruct.
"When ROS-modified compounds are incorporated into a DNA strand, they cause frayed ends that can’t be properly glued together during DNA repair," Wilson said. "This gap or break in DNA can initiate cell death."
The double-edged sword
The pressure that ROS places on cells is called oxidative stress, and it happens all the time. The body takes advantage of the killing power of ROS in a series of steps known as innate immunity, or the natural immunity a person is born with.
For example, Wilson explained that when a bacterium enters the body, a white blood cell activates a special immune cell called a macrophage. The macrophage douses the bacterium with ROS. Just as ROS causes breaks in human cellular and mitochondrial DNA, it will go to work breaking the bacterium’s DNA. That way, the macrophage kills the bacterium before engulfing it.
The scheme is a wonderfully resourceful way to kill living things that could make a person sick, but what happens when the invader is not alive? Take, for example, the particles in cigarette smoke or smog. When these small pieces of matter enter human lung cells, they trigger a similar ROS response by macrophages.
The macrophages use the same mechanism to get rid of invaders. But in this case, the oxidative stress eventually leads to fibrosis, which is the thickening or scarring of tissue seen in chronic lung disease. Wilson mentioned other conditions, such as cataracts, cardiovascular disease, and some neurodegenerative disorders, that are also linked to the effects of oxidative stress.
Understanding the mysterious mitochondria
Wilson said the research described in the new paper demonstrates a subtle way cells can accommodate the damage ROS inflicts on them. The self-destruction of an individual cell as a result of oxidative stress is a less extreme outcome, compared with the result of exposure to a strong oxidizing agent, such as bleach. In that case, all of the cells in the mix — both the body’s cells and the pathogens — would die.
NIEHS mitochondrial expert Bill Copeland, Ph.D., was not involved in this research, but acknowledges the part that mitochondria play in this molecular balancing act. He said, "We know that the mitochondria probably produce the majority of ROS in a cell, so fully understanding their function may lead to the root of human illness."
Citation: Caglayan M, Horton JK, Dai DP, Stefanick DF, Wilson SH. 2017. Oxidized nucleotide insertion by pol beta confounds ligation during base excision repair. Nat Commun 8:14045.