Why too much DNA repair can injure tissue

DNA-repair enzymes help cells to avoid damage to their genomes, which are produced as a normal by-product of cell activity and may also be due to environmental toxins.

However, in some cases, repair of DNA can be harmful to cells, causing an inflammatory response which can cause severe tissue damage.

MIT Professor Leona Samson has now determined that inflammation is a major component in the way the damage occurs in photoreceptor cells in the retina of the rats.

About 10 years ago, he and his colleagues found that excessive activity of DNA-repair systems could lead to retinal damage and blindness in rats.

In this process, the major enzyme, known as egg glycosylase, may also damage other tissues if hyperactive.

Says Samson, professor of biology and professor biography and study, "It is despite the fact that in some circumstances it may actually be harmful to your safety, despite inflammation, when it becomes overactive."

Egg glycosylase helps to cure DNA damage due to a class of drugs known as alkylating agents, which are commonly used as chemotherapy drugs and can be used as tobacco smoke and fuel exhaust pollutants Are also found in Retinal damage from these drugs has not been seen in human patients, but alkylating agents can produce similar damage in other human tissues, Sanskar says.

New studies show how excessive fire leads to cell death, suggests potential targets for drugs that can prevent such damage.

Maritermeela Alloka, a former MIT postdoc, is the chief author of the study who appears in the issue of Science Signaling on February 12.

A vicious circle

In a 2009 study, Samson and his colleagues found that the rate of retinal damage in mice was very high due to the relatively low level of exposure to an alkaline agent.

Alkylating agents produce specific types of DNA damage, and AAG glycosylase usually starts repairing such damage.

However, in some types of cells that have a high level of Aag, such as mouse photoreceptors, excessive enzymes stop a series of events that eventually lead to cell death.

In the new study, the researchers wanted to find out how it happened.

They knew that the fire was very active in the affected cells, but they did not know how this cell is moving towards death or what type of cell is killing.

Researchers initially suspected that it is apoptosis, a type of programmed cell death in which a dead cell gradually breaks down and becomes absorbed by other cells.

However, they soon found evidence that another type of cell death is called necrosis for most of the damage.

When Aig starts trying to repair DNA damage due to the alkylating agent, it cuts down many damaged DNA bases that activates an enzyme called PARP, which induces necrosis.

During this type of cell death, the cells break down and expel their contents, which alert the immune system that something is wrong.

One of the cells secreted by dying cells, known as HMGB1, stimulates the production of chemicals that attract immune cells called macrophages, which in particular block the photoreceptor layer of the retina.

These macrophages produce highly reactive oxygen species - the molecules that cause more damage and make the environment more provocative.

This in turn causes more DNA damage, which is recognized by the fire.

Samson says, because the situation worsens because fire glycosyls will work on the wounds caused by inflammation, so you get a vicious cycle, and DNA repair performs maximum degradation and necrosis in the photoreceptor layer, "Samson it is said.

There is no such thing in rats, which lack deficiency or PARP, and it does not occur in other cells of the eye or in other tissues of the body.

"It surprises me how this is broken, other cells in the retina are not affected at all, and they should experience the same amount of DNA damage.

Therefore, one possibility is that they do not express AAG, While photoreceptor cells do it, "says Samson.

"These molecular studies are exciting because they have helped to define the underlying pathophysiology associated with retinal damage," says Ben Van Houten, a professor of pharmacology and chemical biology at the University of Pittsburgh, who were not involved in the study.

DNA repair is essential for the faithful succession of the genetic material of a cell.

However, some DNA repair enzymes can produce toxic intermediates with very action which increases the risk for genotoxic agents."

Different effects

Researchers also found that swelling and necrosis of the retina were more serious in male rats compared to female rats.

They suspect that estrogen, which can interfere with PARP activity, can help to suppress inflammation and the path leading to cell death.

Samson's Lab has previously found that Egg activity can harm the brain during a stroke, in rats.

This study has shown that the activity also damages inflammation and tissue damage in the liver and kidney after the lack of oxygen.

Mouse cerebellum and some pancreatic and bone marrow cells have also seen AAG-driven cell death.

The effects of mouth overactivity have been studied very little in humans, but there is evidence that healthy levels of enzyme vary greatly in healthy individuals, suggesting that different people have different effects Can.

"Probably there are some cell types in the human body that the mouse will react like a photoreceptor," says Samson. "They can not be the only set of cells."

Research was funded by the National Institutes of Health.

Why too much DNA repair can injure tissue