Head trauma damages DNA repair mechanism

July 09, 1999

Last year, researchers at the University of Pennsylvania Medical Center found that brain cells continue to die for weeks to months after sustaining injury. Now, these investigators have found that a cell's ability to detect damage to DNA in its nucleus is also impaired for months after an injury. The DNA in human cells is assaulted everyday by all sorts of damaging agents -- ultraviolet radiation, chemicals, and heat, for example -- but normally the body has a vigilant surveillance system in place to detect damage and quickly repair it.

"This is the first paper to show that brain trauma alters the specific pathways for recognizing DNA damage and initiating the DNA repair process," says senior author Tracy K. McIntosh, PhD, professor of neurosurgery, bioengineering, and pharmacology and director of Penn's Head Injury Center. McIntosh and colleagues report their findings in the current issue of the Journal of Neurochemistry.

Using a model of experimental brain injury in rats, McIntosh and colleagues showed that the enzyme poly(ADP-ribose) polymerase (PARP), which repairs specific cuts in the DNA helix, is activated by brain cells as early as 30 minutes after an injury. But, at seven days post-injury, destruction of PARP becomes pronounced, which suggests that DNA repair is initiated in the acute post-injury phase, but subsequent DNA repair may be weakened. The researchers hypothesize that this might be due to cell-death-mediated degradation of PARP, which ultimately adversely affects the repair of damaged DNA.

Essentially, an injured cell's internal observation system for detecting damage breaks down and cellular repair crews are never called into action. "If the body can't detect that DNA has been fragmented, the repair mechanisms that we normally have in place can't do their job," says McIntosh. "So, all the efforts we're using to save cells after brain damage become useless, because if the DNA is damaged, the cell can't make proteins and will eventually die."

Calcium enters cells in massive amounts following injury, with devastating effects. As a result, harsh biochemicals called oxygen free radicals punch holes in the cell membrane, and intracellular proteases called calpains attack the cell's internal skeleton, both of which cause the cell to collapse. Immediately after trauma, various drugs are given to stop calcium entry.

But, this cascade of events occurs outside the nucleus, away from the genome. "If we go to great lengths to protect the cell and in the meantime the DNA is also damaged due to trauma, that cell is doomed and all of our heroic efforts will have been in vain," notes McIntosh.

PARP production may also be detrimental for the injured brain because its activation uses up an enormous amount of energy, draining much-needed biochemical fuel from tissue repair, which further contributes to cell death. McIntosh's lab is currently evaluating the energy-draining theory by pharmacologically inhibiting PARP in rodents.

Michelle LaPlaca, PhD, a former post-doctoral fellow in McIntosh's lab was lead author of the study. Penn colleagues Ramesh Raghupathi, PhD, assistant professor of neurosurgery, and Kathryn Saatman, PhD, research assistant professor of neurosurgery, also collaborated on this study. This research was supported by grants from the National Institutes of Health.
Editor's Note: Dr. McIntosh can be reached at 215-573-3156 or mcintosh@eniac.seas.upenn.edu

The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the largest absolute growth in funding for research and training among all 125 medical schools in the country since 1991. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page www.med.upenn.edu, to EurekAlert! http://www.eurekalert.org, an Internet resource sponsored by the American Association for the Advancement of Science.

University of Pennsylvania School of Medicine

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