Enzyme that Repairs DNA Is Blocked in Aging Cells

Newswise — Improving aging cells' ability to repair their own damaged DNA could potentially help prevent or treat cancer, Alzheimer's disease, Parkinson's disease and other illnesses caused by genetic defects.

Researchers at the University of Texas Medical Branch at Galveston (UTMB) are contributing to that prospect with a new study exploring why the aging body is unable to defend against DNA damage in the power plants that fuel cells' growth and activity, known as the mitochondria.

The UTMB study is being published online the week of Sept. 1 in the Proceedings of the National Academy of Sciences. The article is titled "Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases."

In the study, UTMB Professor Sankar Mitra and colleagues document a defect in the body's self-defense mechanism that wards off genetic mutations that occur with aging.

Inside a cell, both the nucleus and the cell's many mitochondria contain DNA. As cells age, genetic changes (mutations) take place continuously. Some of these mutations are caused during respiration by harmful byproducts (reactive oxygen species or oxygen radicals) of oxygen that we inhale. Mitochondria are the major cellular source of oxygen species and the main cellular target of oxidative damage.

Simultaneously, the body has an intrinsic DNA repair function that repairs the damage caused by these bad byproducts. As the body's cells are relentlessly bombarded with these harmful oxygen radicals, the body's repair mechanism is constantly at work fixing this DNA damage, Mitra explains.

In young cells, the repair activity—carried out by repair enzymes—typically repairs most of the damage inflicted by oxygen radicals. But as cells age, their repair system becomes inefficient, failing to correct many of the mutations to our genetic code.

In their study, Mitra and his colleagues analyzed why this repair process becomes less effective in fixing DNA damage in the mitochondria as cells age. The UTMB study was the first look at how age decreases the mitochondria's ability to transport the repair enzyme to the mitochondria's DNA.

In their findings, Mitra and his colleagues identified a roadblock that prevents much of the repair enzyme activity from reaching the site of the DNA damage in aging cells' mitochondria. In old cells, about half of the repair enzyme activity is stuck outside the mitochondria and can't reach the DNA in order to repair it. That means repair activity isn't present where it's needed, the UTMB study found.

Why the repair enzymes are stuck outside the mitochondria is fodder for future research. This so-called roadblock isn't a physical barrier but a biochemical one. The barrier represents the mitochondria's decreasing ability to transport the repair enzyme to the DNA, Mitra said. This blocked transit passage to the mitochondria happens only in older cells. In young cells, almost all of the repair activity cuts through the mitochondria's membrane to reach the damaged DNA.

"As we get older, our mitochondria become less efficient," Mitra said.

Next, researchers must test if this finding applies to all types of repair proteins, or only to the type of repair enzyme the researchers studied. If it is a general phenomenon that cuts across different types of repair enzymes, more research must be done to discern what causes the mitochondria to lose the ability to transport repair enzymes.

The UTMB study is funded by a program project from the National Institute of Aging and by the National Cancer Institute of the National Institutes of Health.

The study builds on Mitra's previous research on repair enzymes. The type of DNA damage Mitra studied is caused by oxygen, which the body turns into water during respiration. Oxygen radicals react with everything in the body. Many scientists believe it is these reactions that lead to the genetic mutations.

"Oxygen can be very toxic," Mitra said. "It is one of the most dangerous chemicals, even though it is also essential for our survival."

In addition to Mitra, the paper's authors are Bartosz Szczesny, a postdoctoral associate who performed the experiments with Istvan Boldogh, an associate professor of microbiology. Tapas K. Hazra, an assistant professor of biochemistry, and John Papaconstantinou, a professor of biochemistry, are also coauthors of this study.